1
|
Binns TC, Eaton DA, Akiki DV, Deschenes E, Piotrowski-Daspit AS, Bracaglia LG, Hendrickson JE, Saltzman WM. Cellular determinants influence the red blood cell adsorption efficiency of poly(amine- co-ester) nanoparticles. SCIENCE ADVANCES 2025; 11:eadt8637. [PMID: 40315323 PMCID: PMC12047439 DOI: 10.1126/sciadv.adt8637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 03/27/2025] [Indexed: 05/04/2025]
Abstract
Many poly(amine-co-ester) (PACE) nanoparticles, drug delivery vehicles for nucleic acid and small molecule cargoes, accumulate in the liver and spleen following intravenous administration, limiting delivery to nonhepatosplenic tissues. Red blood cell (RBC) hitchhiking, a strategy in which nanoparticles are nonspecifically adsorbed to RBCs prior to administration, has been used to modulate nanoparticle biodistribution, enabling enrichment in organs immediately downstream from the site of vascular infusion. We find that scarcely investigated cellular determinants-namely, storage duration, membrane stiffness, and membrane-bound sialic acid quantity-substantially affect PACE nanoparticle adsorption efficiency. Following development of an optimized adsorption protocol, RBC hitchhiking was shown to enhance PACE nanoparticle cargo delivery to pulmonary tissue while also increasing exposure to other assayed organs. These findings inform future RBC hitchhiking study design, implicate cellular variables as potential obstacles or boons to clinical translation, and demonstrate the delivery of nucleic acids using this strategy with the PACE nanoparticle platform.
Collapse
Affiliation(s)
- Thomas C. Binns
- Department of Laboratory Medicine, Yale University, New Haven, CT 06520, USA
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
| | - David A. Eaton
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
- Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Dana V. Akiki
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
| | - Emily Deschenes
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
| | - Alexandra S. Piotrowski-Daspit
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Laura G. Bracaglia
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
- Department of Chemical and Biological Engineering, Villanova University, Villanova, PA 19085, USA
| | - Jeanne E. Hendrickson
- Department of Laboratory Medicine, Yale University, New Haven, CT 06520, USA
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA
| | - W. Mark Saltzman
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
- Department of Chemical & Environmental Engineering, Yale University, New Haven, CT 06520, USA
- Department of Cellular & Molecular Physiology, Yale University, New Haven, CT 06520, USA
| |
Collapse
|
2
|
Cheng Y, Dang S, Zhang Y, Chen Y, Yu R, Liu M, Jin S, Han A, Katz S, Wang S. Sequencing-free whole genome spatial transcriptomics at molecular resolution in intact tissue. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.06.641951. [PMID: 40161724 PMCID: PMC11952344 DOI: 10.1101/2025.03.06.641951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Recent breakthroughs in spatial transcriptomics technologies have enhanced our understanding of diverse cellular identities, compositions, interactions, spatial organizations, and functions. Yet existing spatial transcriptomics tools are still limited in either transcriptomic coverage or spatial resolution. Leading spatial-capture or spatial-tagging transcriptomics techniques that rely on in-vitro sequencing offer whole-transcriptome coverage, in principle, but at the cost of lower spatial resolution compared to image-based techniques. In contrast, high-performance image-based spatial transcriptomics techniques, which rely on in situ hybridization or in situ sequencing, achieve single-molecule spatial resolution and retain sub-cellular morphologies, but are limited by probe libraries that target only a subset of the transcriptome, typically covering several hundred to a few thousand transcript species. Together, these limitations hinder unbiased, hypothesis-free transcriptomic analyses at high spatial resolution. Here we develop a new image-based spatial transcriptomics technology termed Reverse-padlock Amplicon Encoding FISH (RAEFISH) with whole-genome level coverage while retaining single-molecule spatial resolution in intact tissues. We demonstrate image-based spatial transcriptomics targeting 23,000 human transcript species or 22,000 mouse transcript species, including nearly the entire protein-coding transcriptome and several thousand long-noncoding RNAs, in single cells in cultures and in tissue sections. Our analyses reveal differential subcellular localizations of diverse transcripts, cell-type-specific and cell-type-invariant tissue zonation dependent transcriptome, and gene expression programs underlying preferential cell-cell interactions. Finally, we further develop our technology for direct spatial readout of gRNAs in an image-based high-content CRISPR screen. Overall, these developments provide the research community with a broadly applicable technology that enables high-coverage, high-resolution spatial profiling of both long and short, native and engineered RNA species in many biomedical contexts.
Collapse
Affiliation(s)
- Yubao Cheng
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Shengyuan Dang
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
- These authors contributed equally to this work
| | - Yuan Zhang
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
- These authors contributed equally to this work
| | - Yanbo Chen
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Ruihuan Yu
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
- Present Address: Department of Biological Sciences, Columbia University, New York, NY 10027, USA
| | - Miao Liu
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Shengyan Jin
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Ailin Han
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Samuel Katz
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Siyuan Wang
- Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
- M.D.-Ph.D. Program, Yale University, New Haven, CT 06510, USA
- Yale Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT 06510, USA
- Molecular Cell Biology, Genetics and Development Program, Yale University, New Haven, CT 06510, USA
- Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA
- Biochemistry, Quantitative Biology, Biophysics, and Structural Biology Program, Yale University, New Haven, CT 06510, USA
- Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06510, USA
- Yale Liver Center, Yale University School of Medicine, New Haven, CT 06510, USA
- Lead contact
| |
Collapse
|
3
|
Jung SC, Kang D, Ko EA. Roles of PDGF/PDGFR signaling in various organs. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2025; 29:139-155. [PMID: 39482238 PMCID: PMC11842291 DOI: 10.4196/kjpp.24.309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/03/2024] [Accepted: 10/07/2024] [Indexed: 11/03/2024]
Abstract
Platelet-derived growth factors (PDGFs) ligands and their corresponding receptors, PDGF receptor (PDGFR)α and PDGFRβ, play a crucial role in controlling diverse biological functions, including cell growth, viability and migration. These growth factors bind to PDGFRs, which are receptor tyrosine kinases present on the surface of target cells. The interaction between PDGFs and PDGFRs induces receptor dimerization and subsequent activation through auto-phosphorylation, which in turn triggers a cascade of intracellular signaling pathways. PDGF/PDGFR signaling is essential for maintaining normal physiological functions, including tissue regeneration and growth. However, dysregulation of this signaling pathway leads to pathological conditions, including fibrosis, atherosclerosis, and cancer development in various organs. The pathological impact of PDGF/PDGFR signaling primarily stems from its capacity to promote excessive cell proliferation, enhanced migration, and increased extracellular matrix deposition, resulting in tissue overgrowth, scarring, and abnormal vessel formation. These processes are integral to the pathogenesis of fibrotic, neoplastic, and vascular disorders. Therefore, understanding these pathways is crucial for developing targeted treatments designed to inhibit PDGF/PDGFR signaling in these diseases. This review delves into the dual role of PDGF/PDGFR signaling in both physiological and pathophysiological contexts across different organs and provides insights into current pharmacological therapies designed to target the PDGF signaling pathway.
Collapse
Affiliation(s)
- Sung-Cherl Jung
- Department of Physiology, College of Medicine, Jeju National University, Jeju 63243, Korea
| | - Dawon Kang
- Department of Physiology, College of Medicine and Institute of Medical Sciences, Gyeongsang National University, Jinju 52727, Korea
| | - Eun-A Ko
- Department of Physiology, College of Medicine, Jeju National University, Jeju 63243, Korea
| |
Collapse
|
4
|
Lu Y, Liang X, Song J, Guan Y, Yang L, Shen R, Niu Y, Guo Z, Zhu N. Niclosamide modulates phenotypic switch and inflammatory responses in human pulmonary arterial smooth muscle cells. Mol Cell Biochem 2025; 480:1583-1593. [PMID: 38980591 DOI: 10.1007/s11010-024-05061-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 06/29/2024] [Indexed: 07/10/2024]
Abstract
Excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) represent key steps of pulmonary vascular remodeling, leading to the development of pulmonary arterial hypertension (PAH) and right ventricular failure. Niclosamide (NCL), an FDA-approved anthelmintic, has been shown to regulate cell proliferation, migration, invasion, and apoptosis through a variety of signaling pathways. However, its role on modulating the phenotypic switch and inflammatory responses in PASMCs remains unclear. In this study, cell proliferation assay showed that NCL inhibited PDGF-BB induced proliferation of human PASMCs in a dose-dependent manner. Western blot analysis further confirmed a notable reduction in the expression of cyclin D1 and PCNA proteins. Subsequently, flow cytometry analysis demonstrated that NCL induced an increased percentage of cells in the G1 phase while promoting apoptosis in PASMCs. Moreover, both scratch wound assay and transwell assay confirmed that NCL decreased PDGF-BB-induced migration of PASMCs. Mechanistically, western blot revealed that pretreatment of PASMCs with NCL markedly restored the protein levels of SMA, SM22, and calponin, while reducing phosphorylation of P38/STAT3 signaling in the presence of PDGF-BB. Interestingly, macrophages adhesion assay showed that NCL markedly reduced recruitment of Calcein-AM labeled RAW264.7 by TNFα-stimulated PASMCs. Western blot revealed that NCL suppressed TNFα-induced expression of both of VCAM-1 and ICAM-1 proteins. Furthermore, pretreatment of PASMCs with NCL significantly inhibited NLRP3 inflammasome activity through reducing NLRP3, AIM2, mature interleukin-1β (IL-β), and cleaved Caspase-1 proteins expression. Together, these results suggested versatile effects of NCL on controlling of proliferation, migration, and inflammatory responses in PASMCs through modulating different pathways, indicating that repurposing of NCL may emerge as a highly effective drug for PAH treatment.
Collapse
Affiliation(s)
- Yuwen Lu
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Xiaogan Liang
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Jingwen Song
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Yugen Guan
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Liang Yang
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Rongrong Shen
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Yunpu Niu
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Zhifu Guo
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China.
| | - Ni Zhu
- Department of Cardiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China.
| |
Collapse
|
5
|
Lin D, Hu L, Wei D, Li Y, Yu Y, Wang Q, Sun X, Shen Y, Yu Y, Li K, Zhang Z, Cao Y, Li J, Li Y, Fulton D, Chen J, Wang J, Huang H, Chen F. Peli1 Deficiency in Macrophages Attenuates Pulmonary Hypertension by Enhancing Foxp1-Mediated Transcriptional Inhibition of IL-6. Hypertension 2025; 82:445-459. [PMID: 39618410 DOI: 10.1161/hypertensionaha.124.23542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 11/13/2024] [Indexed: 02/21/2025]
Abstract
BACKGROUND The infiltration of macrophages into the lungs is a common characteristic of perivascular inflammation, contributing to vascular remodeling in pulmonary hypertension (PH). Peli1 (pellino E3 ubiquitin-protein ligase 1) plays a critical role in regulating the production of proinflammatory cytokines and the polarization of macrophages in various diseases. However, the role of Peli1 in PH remains to be investigated. METHODS The expression and biological function of Peli1 were investigated in both human and experimental models of PH. Peli1-deficient mice and bone marrow transplant mice were utilized to explore the roles of Peli1 in macrophages in vivo. Proteomic analysis and molecular biology techniques were used to uncover the underlying mechanisms. RESULTS The upregulation of Peli1 in the lungs and alveolar macrophages was observed in hypoxia-treated mice. Peli1 knockout mice and myeloid Peli1-deficient mice significantly ameliorated hypoxia-induced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling. Mechanistically, Peli1 facilitated the ubiquitination and subsequent proteasomal degradation of Foxp1 (forkhead box p1), thereby alleviating its suppression of IL (interleukin)-6 transcription and contributing to macrophage activation. Furthermore, myeloid Foxp1 deficiency partially eliminates the protective effect of myeloid Peli1 deficiency in hypoxia-induced PH mice. CONCLUSIONS Our findings demonstrate that the Peli1-Foxp1-IL-6 pathway plays a crucial role in macrophage activation and recruitment during the development of PH, underscoring the potential of Peli1 as a therapeutic target for PH.
Collapse
Affiliation(s)
- Donghai Lin
- Department of Forensic Medicine (D.L., L.H., Yan Li, Yanfang Yu, Y.S., Youjia Yu, K.L., Z.Z., Y.C., J.W., H.H., F.C.), Nanjing Medical University, China
| | - Li Hu
- Department of Forensic Medicine (D.L., L.H., Yan Li, Yanfang Yu, Y.S., Youjia Yu, K.L., Z.Z., Y.C., J.W., H.H., F.C.), Nanjing Medical University, China
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine (L.H., J.L., Yuehua Li, J.W., F.C.), Nanjing Medical University, China
| | - Dong Wei
- The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center (D.W., J.C., F.C.), Nanjing Medical University, China
| | - Yan Li
- Department of Forensic Medicine (D.L., L.H., Yan Li, Yanfang Yu, Y.S., Youjia Yu, K.L., Z.Z., Y.C., J.W., H.H., F.C.), Nanjing Medical University, China
| | - Yanfang Yu
- Department of Forensic Medicine (D.L., L.H., Yan Li, Yanfang Yu, Y.S., Youjia Yu, K.L., Z.Z., Y.C., J.W., H.H., F.C.), Nanjing Medical University, China
| | - Qiang Wang
- Department of Rheumatology, First Affiliated Hospital of Nanjing Medical University, China (Q.W., X.S.)
| | - Xiaoxuan Sun
- Department of Rheumatology, First Affiliated Hospital of Nanjing Medical University, China (Q.W., X.S.)
| | - Yueyao Shen
- Department of Forensic Medicine (D.L., L.H., Yan Li, Yanfang Yu, Y.S., Youjia Yu, K.L., Z.Z., Y.C., J.W., H.H., F.C.), Nanjing Medical University, China
| | - Youjia Yu
- Department of Forensic Medicine (D.L., L.H., Yan Li, Yanfang Yu, Y.S., Youjia Yu, K.L., Z.Z., Y.C., J.W., H.H., F.C.), Nanjing Medical University, China
| | - Kai Li
- Department of Forensic Medicine (D.L., L.H., Yan Li, Yanfang Yu, Y.S., Youjia Yu, K.L., Z.Z., Y.C., J.W., H.H., F.C.), Nanjing Medical University, China
| | - Zhiwei Zhang
- Department of Forensic Medicine (D.L., L.H., Yan Li, Yanfang Yu, Y.S., Youjia Yu, K.L., Z.Z., Y.C., J.W., H.H., F.C.), Nanjing Medical University, China
| | - Yue Cao
- Department of Forensic Medicine (D.L., L.H., Yan Li, Yanfang Yu, Y.S., Youjia Yu, K.L., Z.Z., Y.C., J.W., H.H., F.C.), Nanjing Medical University, China
| | - Jiantao Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine (L.H., J.L., Yuehua Li, J.W., F.C.), Nanjing Medical University, China
| | - Yuehua Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine (L.H., J.L., Yuehua Li, J.W., F.C.), Nanjing Medical University, China
| | - David Fulton
- Vascular Biology Center, Medical College of Georgia at Augusta University, GA (D.F., F.C.)
| | - Jingyu Chen
- The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center (D.W., J.C., F.C.), Nanjing Medical University, China
| | - Jie Wang
- Department of Forensic Medicine (D.L., L.H., Yan Li, Yanfang Yu, Y.S., Youjia Yu, K.L., Z.Z., Y.C., J.W., H.H., F.C.), Nanjing Medical University, China
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine (L.H., J.L., Yuehua Li, J.W., F.C.), Nanjing Medical University, China
| | - Huijie Huang
- Department of Forensic Medicine (D.L., L.H., Yan Li, Yanfang Yu, Y.S., Youjia Yu, K.L., Z.Z., Y.C., J.W., H.H., F.C.), Nanjing Medical University, China
| | - Feng Chen
- Department of Forensic Medicine (D.L., L.H., Yan Li, Yanfang Yu, Y.S., Youjia Yu, K.L., Z.Z., Y.C., J.W., H.H., F.C.), Nanjing Medical University, China
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine (L.H., J.L., Yuehua Li, J.W., F.C.), Nanjing Medical University, China
- The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center (D.W., J.C., F.C.), Nanjing Medical University, China
- Vascular Biology Center, Medical College of Georgia at Augusta University, GA (D.F., F.C.)
| |
Collapse
|
6
|
Park JS, Choi YH, Min JY, Lee J, Shim G. Fundamental and Targeted Approaches in Pulmonary Arterial Hypertension Treatment. Pharmaceutics 2025; 17:224. [PMID: 40006591 PMCID: PMC11859843 DOI: 10.3390/pharmaceutics17020224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/27/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
Pulmonary arterial hypertension (PAH) is a chronic and progressive disease marked by vascular remodeling, inflammation, and smooth muscle cell proliferation, with limited treatment options focused primarily on symptom management. The multifactorial nature of PAH, encompassing genetic, autoimmune, and connective tissue contributions, complicates its treatment, while irreversible vascular changes, such as fibrosis, remain unaddressed by current therapies. Fundamental research on molecular pathways and targeted delivery systems has paved the way for advanced therapeutic strategies that aim to modify disease progression rather than merely manage symptoms. Nanoparticle-based drug delivery systems, leveraging controlled release and pulmonary targeting, offer a promising avenue to overcome these challenges. Such systems enable precise localization to pulmonary vasculature, minimize systemic side effects, and support emerging approaches like gene therapy and combination treatments. Future research should focus on refining nanoparticle formulations for personalized medicine, optimizing inhalation delivery systems, and integrating multi-target approaches to achieve curative outcomes in PAH. This review explores pathophysiology of PAH, current pharmacological strategies, and innovative nanoparticle-based therapies, emphasizing their potential to transform PAH treatment and address its underlying mechanisms.
Collapse
Affiliation(s)
- Ji Su Park
- School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea; (J.S.P.); (Y.H.C.); (J.-Y.M.); (J.L.)
- Integrative Institute of Basic Sciences, Soongsil University, Seoul 06978, Republic of Korea
| | - Yong Hwan Choi
- School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea; (J.S.P.); (Y.H.C.); (J.-Y.M.); (J.L.)
| | - Ji-Young Min
- School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea; (J.S.P.); (Y.H.C.); (J.-Y.M.); (J.L.)
| | - Jaeseong Lee
- School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea; (J.S.P.); (Y.H.C.); (J.-Y.M.); (J.L.)
| | - Gayong Shim
- School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea; (J.S.P.); (Y.H.C.); (J.-Y.M.); (J.L.)
- Integrative Institute of Basic Sciences, Soongsil University, Seoul 06978, Republic of Korea
| |
Collapse
|
7
|
Liu Y, Ma X, Lei L, Wang L, Deng Q, Lu H, Li H, Tian S, Qin X, Zhang W, Sun Y. Smooth Muscle Cell-Specific LKB1 Protects Against Sugen 5416/Hypoxia-induced Pulmonary Hypertension through Inhibition of BMP4. Am J Respir Cell Mol Biol 2025; 72:169-180. [PMID: 39236291 DOI: 10.1165/rcmb.2023-0430oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 09/05/2024] [Indexed: 09/07/2024] Open
Abstract
Pulmonary hypertension (PH) is a life-threatening syndrome associated with hyperproliferation of pulmonary artery smooth muscle cells (PASMCs), which exhibit features similar to those of cancer cells. Currently, there is no curative treatment for PH. LKB1 is known as a tumor suppressor gene with an antiproliferative effect on cancer cells. However, its role and mechanism in the development of PH remain unclear. Gain- and loss-of-function strategies were used to elucidate the mechanisms of LKB1 in regulating the occurrence and progression of PH. Sugen 5416/hypoxia (SuHx) PH model was utilized for in vivo study. We observed a decreased expression of LKB1 not only in the lung vessels of the SuHx mouse model but also in human PASMCs (HPASMCs) exposed to hypoxia. Smooth muscle-specific LKB1 knockout significantly aggravated SuHx-induced PH in mice. RNA-sequencing analysis revealed a substantial increase in bone morphogenetic protein 4 (BMP4) in the aortas of LKB1SMKO mice compared with controls, identifying BMP4 as a novel target of LKB1. LKB1 knockdown in HPASMCs cultured under hypoxic conditions increased BMP4 protein level and HPASMC proliferation and migration. The coimmunoprecipitation analysis revealed that LKB1 directly modulates BMP4 protein degradation through phosphorylation. Therapeutically, suppressing BMP4 expression in smooth muscle cells alleviates PH in LKB1SMKO mice. Our findings demonstrate that LKB1 attenuates PH by enhancing the lysosomal degradation of BMP4, thus suppressing the proliferation and migration of HPASMCs. Modulating the LKB1-BMP4 axis in smooth muscle cells could be a promising therapeutic strategy of PH.
Collapse
MESH Headings
- Animals
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/pathology
- Hypertension, Pulmonary/chemically induced
- Hypertension, Pulmonary/prevention & control
- Humans
- Bone Morphogenetic Protein 4/metabolism
- Bone Morphogenetic Protein 4/antagonists & inhibitors
- Bone Morphogenetic Protein 4/genetics
- Protein Serine-Threonine Kinases/metabolism
- Protein Serine-Threonine Kinases/genetics
- Mice
- AMP-Activated Protein Kinase Kinases
- Mice, Knockout
- Hypoxia/complications
- Hypoxia/metabolism
- Pulmonary Artery/pathology
- Pulmonary Artery/metabolism
- Mice, Inbred C57BL
- Cell Proliferation
- Male
- Muscle, Smooth, Vascular/metabolism
- Cell Hypoxia
- Disease Models, Animal
- AMP-Activated Protein Kinases
Collapse
Affiliation(s)
- Yan Liu
- State Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaoping Ma
- State Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
- Department of Obstetrics and Gynecology, Liaocheng People's Hospital, Liaocheng, China
| | - Lingli Lei
- School of Clinical Medical Sciences, Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China; and
| | - Lin Wang
- Department of Cardiology, Jinan Central Hospital, Jinan, China
| | - Qiming Deng
- State Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Hanlin Lu
- State Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Hongxuan Li
- State Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Shuhui Tian
- School of Clinical Medical Sciences, Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China; and
| | - Xiaoteng Qin
- State Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Wencheng Zhang
- State Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Yuanyuan Sun
- State Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| |
Collapse
|
8
|
Zhang JJ, Ye XR, Liu XS, Zhang HL, Qiao Q. Impact of sodium-glucose cotransporter-2 inhibitors on pulmonary vascular cell function and arterial remodeling. World J Cardiol 2025; 17:101491. [PMID: 39866213 PMCID: PMC11755123 DOI: 10.4330/wjc.v17.i1.101491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/02/2024] [Accepted: 12/17/2024] [Indexed: 01/21/2025] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors represent a cutting-edge class of oral antidiabetic therapeutics that operate through selective inhibition of glucose reabsorption in proximal renal tubules, consequently augmenting urinary glucose excretion and attenuating blood glucose levels. Extensive clinical investigations have demonstrated their profound cardiovascular efficacy. Parallel basic science research has elucidated the mechanistic pathways through which diverse SGLT-2 inhibitors beneficially modulate pulmonary vascular cells and arterial remodeling. Specifically, these inhibitors exhibit promising potential in enhancing pulmonary vascular endothelial cell function, suppressing pulmonary smooth muscle cell proliferation and migration, reversing pulmonary arterial remodeling, and maintaining hemodynamic equilibrium. This comprehensive review synthesizes current literature to delineate the mechanisms by which SGLT-2 inhibitors enhance pulmonary vascular cell function and reverse pulmonary remodeling, thereby offering novel therapeutic perspectives for pulmonary vascular diseases.
Collapse
Affiliation(s)
- Jing-Jing Zhang
- Chinese Academy Medical Sciences, Fuwai Yunnan Hospital, Kunming 650000, Yunnan Province, China
- Kunming Medical University, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming 650000, Yunnan Province, China
| | - Xue-Rui Ye
- Chinese Academy Medical Sciences, Fuwai Yunnan Hospital, Kunming 650000, Yunnan Province, China
- Kunming Medical University, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming 650000, Yunnan Province, China
| | - Xue-Song Liu
- Department of Biochemistry, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hao-Ling Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Qian Qiao
- Chinese Academy Medical Sciences, Fuwai Yunnan Hospital, Kunming 650000, Yunnan Province, China
- Kunming Medical University, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming 650000, Yunnan Province, China.
| |
Collapse
|
9
|
Li H, Li X, Sun Y, Zhi Z, Song L, Li M, Feng Y, Zhang Z, Liu Y, Chen Y, Zhao F, Zhu T. The Role of Ion Channels in Pulmonary Hypertension: A Review. Pulm Circ 2025; 15:e70050. [PMID: 39958971 PMCID: PMC11830494 DOI: 10.1002/pul2.70050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 08/16/2024] [Accepted: 01/31/2025] [Indexed: 02/18/2025] Open
Abstract
Pulmonary hypertension (PH) constitutes a critical challenge in cardiopulmonary medicine with a pathogenesis that is multifaceted and intricate. Ion channels, crucial determinants of cellular electrochemical gradient modulation, have emerged as significant participants in the pathophysiological progression of PH. These channels, abundant on the membranes of pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs), pivotally navigate the nuanced interplay of cell proliferation, migration, and endothelial function, each vital to the pulmonary vascular remodeling (PVR) hallmark of PH. Our review delves into the mechanistic insights of potassium, calcium, magnesium, zinc, and chloride ion channels in relation to their involvement in PH. It not only emphasizes the notable advances and discoveries that cast these ion channels as underlying factors in the etiology and exacerbation of PH but also highlights their potential as innovative therapeutic targets.
Collapse
Affiliation(s)
- Han‐Fei Li
- College of PharmacyXinxiang Medical UniversityXinxiangChina
- Henan International Joint Laboratory of Cardiovascular Remodeling and Drug InterventionXinxiangChina
| | - Xin‐Yao Li
- College of PharmacyXinxiang Medical UniversityXinxiangChina
- Henan International Joint Laboratory of Cardiovascular Remodeling and Drug InterventionXinxiangChina
| | - Yu‐Qing Sun
- College of PharmacyXinxiang Medical UniversityXinxiangChina
- Henan International Joint Laboratory of Cardiovascular Remodeling and Drug InterventionXinxiangChina
| | - Ze‐Ying Zhi
- College of PharmacyXinxiang Medical UniversityXinxiangChina
- Henan International Joint Laboratory of Cardiovascular Remodeling and Drug InterventionXinxiangChina
| | - Liao‐Fan Song
- College of PharmacyXinxiang Medical UniversityXinxiangChina
- Henan International Joint Laboratory of Cardiovascular Remodeling and Drug InterventionXinxiangChina
| | - Meng Li
- College of PharmacyXinxiang Medical UniversityXinxiangChina
- Henan International Joint Laboratory of Cardiovascular Remodeling and Drug InterventionXinxiangChina
| | - Yi‐Ming Feng
- College of PharmacyXinxiang Medical UniversityXinxiangChina
- Henan International Joint Laboratory of Cardiovascular Remodeling and Drug InterventionXinxiangChina
| | - Zhi‐Hao Zhang
- College of PharmacyXinxiang Medical UniversityXinxiangChina
- Henan International Joint Laboratory of Cardiovascular Remodeling and Drug InterventionXinxiangChina
| | - Yan‐Feng Liu
- College of PharmacyXinxiang Medical UniversityXinxiangChina
- Henan International Joint Laboratory of Cardiovascular Remodeling and Drug InterventionXinxiangChina
| | - Yu‐Jing Chen
- College of PharmacyXinxiang Medical UniversityXinxiangChina
- Henan International Joint Laboratory of Cardiovascular Remodeling and Drug InterventionXinxiangChina
| | - Fan‐Rong Zhao
- College of PharmacyXinxiang Medical UniversityXinxiangChina
- Henan International Joint Laboratory of Cardiovascular Remodeling and Drug InterventionXinxiangChina
| | - Tian‐Tian Zhu
- College of PharmacyXinxiang Medical UniversityXinxiangChina
- Henan International Joint Laboratory of Cardiovascular Remodeling and Drug InterventionXinxiangChina
- Department of PharmacyThe First Affiliated Hospital of Xinxiang Medical UniversityXinxiangChina
| |
Collapse
|
10
|
Liu Y, Huang J, Li L, Duan Y, Chong BH, Li L, Yang M. Regulatory Effect of PDGF/PDGFR on Hematopoiesis. Semin Thromb Hemost 2024. [PMID: 39608410 DOI: 10.1055/s-0044-1796630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2024]
Abstract
Platelet-derived growth factor (PDGF) is a critical cytokine with substantial regulatory effects on hematopoiesis. Recent research highlights the essential role of PDGF in the modulation of hematopoietic stem/progenitor cells (HSPCs), megakaryocytes/platelets, and thrombopoietin (TPO) synthesis within the bone marrow microenvironment. PDGF directly stimulates the proliferation and differentiation of HSPCs while also inhibiting apoptosis. In addition, PDGF indirectly enhances the production of other growth factors, including granulocyte-macrophage colony-stimulating factors. Further, PDGF regulates TPO production and influences the bone marrow milieu, thus impacting hematopoiesis and platelet formation. Mechanistically, PDGF binds to its receptor, PDGF receptor (PDGFR), thus activating the PDGF/PDGFR signaling pathway. This pathway subsequently activates phosphoinositide 3-kinase/protein kinase B, leading to the activation of downstream cytokines, including c-Fos and NF-E2, while inhibiting caspase-3 activation. Collectively, these actions have prodifferentiation and antiapoptotic effects on megakaryocytes, thereby regulating platelet production. This review provides a comprehensive analysis of the regulatory role of the PDGF/PDGFR axis in hematopoiesis, with a particular focus on platelet production, by summarizing all studies on PDGF/PDGFR from our group and globally.
Collapse
Affiliation(s)
- Yong Liu
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
- Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Junbin Huang
- Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Lindi Li
- Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Yifei Duan
- Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Beng H Chong
- Haematology Research Unit, School of Clinical Medicine, St George and Sutherland Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia
- New South Wales Health Pathology, St George Hospital, Kogarah, New South Wales, Australia
| | - Liang Li
- Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Mo Yang
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
- Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
- Department of Hematology, Affiliated Hospital of Guangdong Medical University (GDMU), Zhanjiang, Guangdong, China
| |
Collapse
|
11
|
Laban H, Siegmund S, Schlereth K, Trogisch FA, Ablieh A, Brandenburg L, Weigert A, De La Torre C, Mogler C, Hecker M, Kuebler WM, Korff T. Nuclear factor of activated T-cells 5 is indispensable for a balanced adaptive transcriptional response of lung endothelial cells to hypoxia. Cardiovasc Res 2024; 120:1590-1606. [PMID: 39107245 DOI: 10.1093/cvr/cvae151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 05/07/2024] [Accepted: 06/01/2024] [Indexed: 08/09/2024] Open
Abstract
AIMS Chronic hypoxia causes detrimental structural alterations in the lung, which may cause pulmonary hypertension and are partially mediated by the endothelium. While its relevance for the development of hypoxia-associated lung diseases is well known, determinants controlling the initial adaptation of the lung endothelium to hypoxia remain largely unexplored. METHODS AND RESULTS We revealed that hypoxia activates the transcription factor nuclear factor of activated T-cells 5 (NFAT5) and studied its regulatory function in murine lung endothelial cells (MLECs). EC-specific knockout of Nfat5 (Nfat5(EC)-/-) in mice exposed to normobaric hypoxia (10% O2) for 21 days promoted vascular fibrosis and aggravated the increase in pulmonary right ventricular systolic pressure as well as right ventricular dysfunction as compared with control mice. Microarray- and single-cell RNA-sequencing-based analyses revealed an impaired growth factor-, energy-, and protein-metabolism-associated gene expression in Nfat5-deficient MLEC after exposure to hypoxia for 7 days. Specifically, loss of NFAT5 boosted the expression and release of platelet-derived growth factor B (Pdgfb)-a hypoxia-inducible factor 1 alpha (HIF1α)-regulated driver of vascular smooth muscle cell (VSMC) growth-in capillary MLEC of hypoxia-exposed Nfat5(EC)-/- mice, which was accompanied by intensified VSMC coverage of distal pulmonary arteries. CONCLUSION Collectively, our study shows that early and transient subpopulation-specific responses of MLEC to hypoxia may determine the degree of organ dysfunction in later stages. In this context, NFAT5 acts as a protective transcription factor required to rapidly adjust the endothelial transcriptome to cope with hypoxia. Specifically, NFAT5 restricts HIF1α-mediated Pdgfb expression and consequently limits muscularization and resistance of the pulmonary vasculature.
Collapse
MESH Headings
- Animals
- Male
- Mice
- Adaptation, Physiological
- Cell Hypoxia
- Cells, Cultured
- Disease Models, Animal
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Gene Expression Regulation
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/genetics
- Hypertension, Pulmonary/pathology
- Hypertension, Pulmonary/physiopathology
- Hypoxia/metabolism
- Hypoxia/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Lung/metabolism
- Lung/blood supply
- Lung/pathology
- Mice, Inbred C57BL
- Mice, Knockout
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Pulmonary Artery/metabolism
- Pulmonary Artery/pathology
- Pulmonary Artery/physiopathology
- Signal Transduction
- Transcription Factors/metabolism
- Transcription Factors/genetics
- Transcription, Genetic
- Vascular Remodeling
- Ventricular Function, Right
Collapse
Affiliation(s)
- Hebatullah Laban
- Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany
- Deutsches Zentrum für Herz-Kreislauf-Forschung e.V. (DZHK), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany
| | - Sophia Siegmund
- Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany
| | - Katharina Schlereth
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany
| | - Felix A Trogisch
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany
- Department of Cardiovascular Physiology and Cardiac Imaging Center, Core Facility Platform Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Alia Ablieh
- Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany
| | - Lennart Brandenburg
- Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany
| | - Andreas Weigert
- Institute of Biochemistry I Pathobiochemistry, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany
| | - Carolina De La Torre
- NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Carolin Mogler
- Institute of Pathology, School of Medicine, Technical University Munich, Munich, Germany
| | - Markus Hecker
- Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany
| | - Wolfgang M Kuebler
- Institute of Physiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
| | - Thomas Korff
- Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany
| |
Collapse
|
12
|
Lewis CV, Garcia AM, Burciaga SD, Posey JN, Jordan M, Nguyen TTN, Stenmark KR, Mickael C, Sul C, Delaney C, Nozik ES. Redistribution of SOD3 expression due to R213G polymorphism affects pulmonary interstitial macrophage reprogramming in response to hypoxia. Physiol Genomics 2024; 56:776-790. [PMID: 39311838 PMCID: PMC11573264 DOI: 10.1152/physiolgenomics.00078.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 08/14/2024] [Accepted: 09/11/2024] [Indexed: 10/25/2024] Open
Abstract
The extracellular isoform of superoxide dismutase (SOD3) is decreased in patients and animals with pulmonary hypertension (PH). The human R213G single-nucleotide polymorphism (SNP) in SOD3 causes its release from tissue extracellular matrix (ECM) into extracellular fluids, without modulating enzyme activity, increasing cardiovascular disease risk in humans and exacerbating chronic hypoxic PH in mice. Given the importance of interstitial macrophages (IMs) to PH pathogenesis, this study aimed to determine whether R213G SOD3 increases IM accumulation and alters IM reprogramming in response to hypoxia. R213G mice and wild-type (WT) controls were exposed to hypobaric hypoxia for 4 or 14 days compared with normoxia. Flow cytometry demonstrated a transient increase in IMs at day 4 in both strains. Contrary to our hypothesis, the R213G SNP did not augment IM accumulation. To determine strain differences in the IM reprogramming response to hypoxia, we performed RNAsequencing on IMs isolated at each timepoint. We found that IMs from R213G mice exposed to hypoxia activated ECM-related pathways and a combination of alternative macrophage and proinflammatory signaling. Furthermore, when compared with WT responses, IMs from R213G mice lacked metabolic remodeling and demonstrated a blunted anti-inflammatory response between the early (day 4) and later (day 14) timepoints. We confirmed metabolic responses using Agilent Seahorse assays, whereby WT, but not R213G, IMs upregulated glycolysis at day 4 that returned to baseline at day 14. Finally, we identify differential regulation of several redox-sensitive upstream regulators that could be investigated in future studies.NEW & NOTEWORTHY Redistributed expression of SOD3 out of tissue ECM due to the human R213G SNP exacerbates chronic hypoxic PH. Highlighting the importance of macrophage phenotype, our findings reveal that the R213G SNP does not exacerbate pulmonary macrophage accumulation in response to hypoxia but influences their metabolic and phenotypic reprogramming. We demonstrate a deficiency in the metabolic response to hypoxic stress in R213G macrophages, associated with weakened inflammatory resolution and activation of profibrotic pathways implicated in PH.
Collapse
Affiliation(s)
- Caitlin V Lewis
- Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Section of Pediatric Critical Care Medicine, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Anastacia M Garcia
- Division of Cardiology, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Samuel D Burciaga
- Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Section of Pediatric Critical Care Medicine, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Janelle N Posey
- Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Section of Neonatology, Department of Pediatrics, Division of Cardiology, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Mariah Jordan
- Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Section of Neonatology, Department of Pediatrics, Division of Cardiology, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Thi-Tina N Nguyen
- Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Section of Pediatric Critical Care Medicine, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Kurt R Stenmark
- Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Section of Pediatric Critical Care Medicine, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Claudia Mickael
- Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Section of Pediatric Critical Care Medicine, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Christina Sul
- Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Section of Pediatric Critical Care Medicine, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Cassidy Delaney
- Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Section of Neonatology, Department of Pediatrics, Division of Cardiology, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Eva S Nozik
- Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Section of Pediatric Critical Care Medicine, Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| |
Collapse
|
13
|
Jia K, Luo X, Yi J, Zhang C. Hormonal influence: unraveling the impact of sex hormones on vascular smooth muscle cells. Biol Res 2024; 57:61. [PMID: 39227995 PMCID: PMC11373308 DOI: 10.1186/s40659-024-00542-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 08/26/2024] [Indexed: 09/05/2024] Open
Abstract
Sex hormones play a pivotal role as endocrine hormones that exert profound effects on the biological characteristics and vascular function of vascular smooth muscle cells (VSMCs). By modulating intracellular signaling pathways, activating nuclear receptors, and regulating gene expression, sex hormones intricately influence the morphology, function, and physiological state of VSMCs, thereby impacting the biological properties of vascular contraction, relaxation, and growth. Increasing evidence suggests that abnormal phenotypic changes in VSMCs contribute to the initiation of vascular diseases, including atherosclerosis. Therefore, understanding the factors governing phenotypic alterations in VSMCs and elucidating the underlying mechanisms can provide crucial insights for refining interventions targeted at vascular diseases. Additionally, the varying levels of different types of sex hormones in the human body, influenced by sex and age, may also affect the phenotypic conversion of VSMCs. This review aims to explore the influence of sex hormones on the phenotypic switching of VSMCs and the development of associated vascular diseases in the human body.
Collapse
Affiliation(s)
- Keran Jia
- Department of Medical Cell Biology and Genetics, School of Basic Medical Sciences, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Xin Luo
- Department of Medical Cell Biology and Genetics, School of Basic Medical Sciences, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Jingyan Yi
- Department of Medical Cell Biology and Genetics, School of Basic Medical Sciences, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, Sichuan, 646000, China.
| | - Chunxiang Zhang
- Department of Cardiology, The Affiliated Hospital, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, Sichuan, 646000, China.
| |
Collapse
|
14
|
Huang W, Zhou H, He Y, Wang A, Wang B, Chen Y, Liu C, Wang H, Xie W, Kong H. A novel PDGFR inhibitor WQ-C-401 prevents pulmonary vascular remodeling in rats with monocrotaline-induced pulmonary arterial hypertension. Exp Cell Res 2024; 441:114154. [PMID: 38996959 DOI: 10.1016/j.yexcr.2024.114154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 07/07/2024] [Accepted: 07/09/2024] [Indexed: 07/14/2024]
Abstract
Platelet-derived growth factor (PDGF) is one of the most important cytokines associated with pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). PDGF receptor (PDGFR) inhibition exerted therapeutic effects on PAH in clinical trials, but serious side effects warrant the withdrawal of existing drugs. In this study, a novel highly selective PDGFR inhibitor WQ-C-401 was developed, and its effects on PDGFR signaling pathway and pulmonary vascular remodeling in PAH were investigated. Cell proliferation assays and Western blot analysis of PDGFRα/β phosphorylation showed that WQ-C-401 inhibited PDGFR-mediated cell proliferation assay and suppressed PDGFR phosphorylation in a concentration-dependent manner. DiscoverX's KinomeScanTM technology confirmed the good kinome selectivity of WQ-C-401 (S score (1) of PDGFR = (0.01)). In monocrotaline (MCT)-induced PAH rats, intragastric administration of WQ-C-401 (25, 50, 100 mg/kg/d) or imatinib (50 mg/kg/d, positive control) significantly decreased right ventricular systolic pressure (RVSP). Histological analysis demonstrated that WQ-C-401 inhibited pulmonary vascular remodeling by reducing muscularization and fibrosis, as well as alleviated right ventricular hypertrophy in MCT-treated rats. In addition, WQ-C-401 suppressed MCT-induced cell hyperproliferation and CD68+ macrophage infiltration around the pulmonary artery. In vitro, WQ-C-401 inhibited PDGF-BB-induced proliferation and migration of human pulmonary arterial smooth muscle cells (PASMCs). Moreover, Western blot analysis showed that WQ-C-401 concertration-dependently inhibited PDGF-BB-induced phosphorylation of ERK1/2 and PDGFRβ Y751, decreased collagen Ⅰ synthesis and increased alpha smooth muscle actin (α-SMA) expression in PASMCs. Collectively, our results suggest that WQ-C-401 is a selective and potent PDGFR inhibitor which could be a promising drug for the therapeutics of PAH by preventing pulmonary vascular remodeling.
Collapse
MESH Headings
- Animals
- Monocrotaline
- Vascular Remodeling/drug effects
- Rats
- Cell Proliferation/drug effects
- Male
- Rats, Sprague-Dawley
- Pulmonary Arterial Hypertension/drug therapy
- Pulmonary Arterial Hypertension/chemically induced
- Pulmonary Arterial Hypertension/metabolism
- Pulmonary Arterial Hypertension/pathology
- Humans
- Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors
- Receptors, Platelet-Derived Growth Factor/metabolism
- Phosphorylation/drug effects
- Pulmonary Artery/drug effects
- Pulmonary Artery/pathology
- Pulmonary Artery/metabolism
- Signal Transduction/drug effects
- Hypertension, Pulmonary/chemically induced
- Hypertension, Pulmonary/drug therapy
- Hypertension, Pulmonary/prevention & control
- Hypertension, Pulmonary/pathology
- Hypertension, Pulmonary/metabolism
- Protein Kinase Inhibitors/pharmacology
- Receptor, Platelet-Derived Growth Factor beta/metabolism
- Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors
Collapse
Affiliation(s)
- Wen Huang
- Department of Pulmonary & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, Jiangsu, PR China
| | - Hong Zhou
- Department of Pulmonary & Critical Care Medicine, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, Jiangsu, PR China
| | - Yiting He
- Department of Pulmonary & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, Jiangsu, PR China
| | - Aoli Wang
- Anhui Province Key Laboratory of Medical Physics & Technology, Institute of Health & Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230031, Anhui, PR China
| | - Beilei Wang
- Anhui Province Key Laboratory of Medical Physics & Technology, Institute of Health & Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230031, Anhui, PR China
| | - Yongfei Chen
- Anhui Province Key Laboratory of Medical Physics & Technology, Institute of Health & Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230031, Anhui, PR China
| | - Chenyang Liu
- Department of Pulmonary & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, Jiangsu, PR China
| | - Hong Wang
- Department of Pulmonary & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, Jiangsu, PR China
| | - Weiping Xie
- Department of Pulmonary & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, Jiangsu, PR China.
| | - Hui Kong
- Department of Pulmonary & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, Jiangsu, PR China.
| |
Collapse
|
15
|
Yamamura A, Fujiwara M, Kawade A, Amano T, Hossain A, Nayeem MJ, Kondo R, Suzuki Y, Inoue Y, Hayashi H, Suzuki S, Sato M, Yamamura H. Corosolic acid attenuates platelet-derived growth factor signaling in macrophages and smooth muscle cells of pulmonary arterial hypertension. Eur J Pharmacol 2024; 973:176564. [PMID: 38614383 DOI: 10.1016/j.ejphar.2024.176564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 03/28/2024] [Accepted: 04/03/2024] [Indexed: 04/15/2024]
Abstract
Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease that is characterized by vascular remodeling of the pulmonary artery. Pulmonary vascular remodeling is primarily caused by the excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), which are facilitated by perivascular inflammatory cells including macrophages. Corosolic acid (CRA) is a natural pentacyclic triterpenoid that exerts anti-inflammatory effects. In the present study, the effects of CRA on the viability of macrophages were examined using monocrotaline (MCT)-induced PAH rats and human monocyte-derived macrophages. Although we previously reported that CRA inhibited signal transducer and activator of transcription 3 (STAT3) signaling and ameliorated pulmonary vascular remodeling in PAH, the inhibitory mechanism remains unclear. Therefore, the underlying mechanisms were investigated using PASMCs from idiopathic PAH (IPAH) patients. In MCT-PAH rats, CRA inhibited the accumulation of macrophages around remodeled pulmonary arteries. CRA reduced the viability of human monocyte-derived macrophages. In IPAH-PASMCs, CRA attenuated cell proliferation and migration facilitated by platelet-derived growth factor (PDGF)-BB released from macrophages and PASMCs. CRA also downregulated the expression of PDGF receptor β and its signaling pathways, STAT3 and nuclear factor-κB (NF-κB). In addition, CRA attenuated the phosphorylation of PDGF receptor β and STAT3 following the PDGF-BB simulation. The expression and phosphorylation levels of PDGF receptor β after the PDGF-BB stimulation were reduced by the small interfering RNA knockdown of NF-κB, but not STAT3, in IPAH-PASMCs. In conclusion, CRA attenuated the PDGF-PDGF receptor β-STAT3 and PDGF-PDGF receptor β-NF-κB signaling axis in macrophages and PASMCs, and thus, ameliorated pulmonary vascular remodeling in PAH.
Collapse
Affiliation(s)
- Aya Yamamura
- Department of Physiology, Aichi Medical University, Nagakute, Aichi, Japan.
| | - Moe Fujiwara
- Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
| | - Akiko Kawade
- Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
| | - Taiki Amano
- Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
| | - Alamgir Hossain
- Department of Physiology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Md Junayed Nayeem
- Department of Physiology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Rubii Kondo
- Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
| | - Yoshiaki Suzuki
- Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
| | - Yasumichi Inoue
- Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
| | - Hidetoshi Hayashi
- Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
| | - Susumu Suzuki
- Research Creation Support Center, Aichi Medical University, Nagakute, Aichi, Japan
| | - Motohiko Sato
- Department of Physiology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Hisao Yamamura
- Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan.
| |
Collapse
|
16
|
Chen X, Yu X, Lian G, Tang H, Yan Y, Gao G, Huang B, Luo L, Xie L. Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates artery remodeling in MCT-induced pulmonary arterial hypertension. Biomed Pharmacother 2024; 174:116505. [PMID: 38574614 DOI: 10.1016/j.biopha.2024.116505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 03/14/2024] [Accepted: 03/27/2024] [Indexed: 04/06/2024] Open
Abstract
Pulmonary arterial hypertension (PAH) was a devastating disease characterized by artery remodeling, ultimately resulting in right heart failure. The aim of this study was to investigate the effects of canagliflozin (CANA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i) with mild SGLT1 inhibitory effects, on rats with PAH, as well as its direct impact on pulmonary arterial smooth muscle cells (PASMCs). PAH rats were induced by injection of monocrotaline (MCT) (40 mg/kg), followed by four weeks of treatment with CANA (30 mg/kg/day) or saline alone. Pulmonary artery and right ventricular (RV) remodeling and dysfunction in PAH were alleviated with CANA, as assessed by echocardiography. Hemodynamic parameters and structural of pulmonary arteriole, including vascular wall thickness and wall area, were reduced by CANA. RV hypertrophy index, cardiomyocyte hypertrophy, and fibrosis were decreased with CANA treatment. PASMCs proliferation was inhibited by CANA under stimulation by platelet-derived growth factor (PDGF)-BB or hypoxia. Activation of AMP kinase (AMPK) was induced by CANA treatment in cultured PASMCs in a time- and concentration-dependent manner. These effects of CANA were attenuated when treatment with compound C, an AMPK inhibitor. Abundant expression of SGLT1 was observed in PASMCs and pulmonary arteries, while SGLT2 expression was undetectable. SGLT1 increased in response to PDGF-BB or hypoxia stimulation, while PASMCs proliferation was inhibited and beneficial effects of CANA were counteracted by knockdown of SGLT1. Our research demonstrated for the first time that CANA inhibited the proliferation of PASMCs by regulating SGLT1/AMPK signaling and thus exerted an anti-proliferative effect on MCT-induced PAH.
Collapse
Affiliation(s)
- Xiaojun Chen
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Xing Yu
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Guili Lian
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Huibin Tang
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yan Yan
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Gufeng Gao
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Bangbang Huang
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Li Luo
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Liangdi Xie
- Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Clinical Research Center for Geriatric Hypertension Disease of Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
| |
Collapse
|
17
|
Saddouk FZ, Kuzemczak A, Saito J, Greif DM. Endothelial HIFα/PDGF-B to smooth muscle Beclin1 signaling sustains pathological muscularization in pulmonary hypertension. JCI Insight 2024; 9:e162449. [PMID: 38652543 PMCID: PMC11141934 DOI: 10.1172/jci.insight.162449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 04/17/2024] [Indexed: 04/25/2024] Open
Abstract
Mechanisms underlying maintenance of pathological vascular hypermuscularization are poorly delineated. Herein, we investigated retention of smooth muscle cells (SMCs) coating normally unmuscularized distal pulmonary arterioles in pulmonary hypertension (PH) mediated by chronic hypoxia with or without Sugen 5416, and reversal of this pathology. With hypoxia in mice or culture, lung endothelial cells (ECs) upregulated hypoxia-inducible factor 1α (HIF1-α) and HIF2-α, which induce platelet-derived growth factor B (PDGF-B), and these factors were reduced to normoxic levels with re-normoxia. Re-normoxia reversed hypoxia-induced pulmonary vascular remodeling, but with EC HIFα overexpression during re-normoxia, pathological changes persisted. Conversely, after establishment of distal muscularization and PH, EC-specific deletion of Hif1a, Hif2a, or Pdgfb induced reversal. In human idiopathic pulmonary artery hypertension, HIF1-α, HIF2-α, PDGF-B, and autophagy-mediating gene products, including Beclin1, were upregulated in pulmonary artery SMCs and/or lung lysates. Furthermore, in mice, hypoxia-induced EC-derived PDGF-B upregulated Beclin1 in distal arteriole SMCs, and after distal muscularization was established, re-normoxia, EC Pdgfb deletion, or treatment with STI571 (which inhibits PDGF receptors) downregulated SMC Beclin1 and other autophagy products. Finally, SMC-specific Becn1 deletion induced apoptosis, reversing distal muscularization and PH mediated by hypoxia with or without Sugen 5416. Thus, chronic hypoxia induction of the HIFα/PDGF-B axis in ECs is required for non-cell-autonomous Beclin1-mediated survival of pathological distal arteriole SMCs.
Collapse
MESH Headings
- Animals
- Humans
- Male
- Mice
- Arterioles/metabolism
- Arterioles/pathology
- Autophagy
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Basic Helix-Loop-Helix Transcription Factors/genetics
- Beclin-1/metabolism
- Beclin-1/genetics
- Disease Models, Animal
- Endothelial Cells/metabolism
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/pathology
- Hypertension, Pulmonary/genetics
- Hypoxia/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Indoles
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Proto-Oncogene Proteins c-sis/metabolism
- Proto-Oncogene Proteins c-sis/genetics
- Pulmonary Artery/metabolism
- Pulmonary Artery/pathology
- Pyrroles
- Signal Transduction
- Vascular Remodeling
Collapse
Affiliation(s)
- Fatima Z. Saddouk
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, and
- Department of Genetics, Yale University, New Haven, Connecticut, USA
| | - Andrew Kuzemczak
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, and
- Department of Genetics, Yale University, New Haven, Connecticut, USA
| | - Junichi Saito
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, and
- Department of Genetics, Yale University, New Haven, Connecticut, USA
| | - Daniel M. Greif
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, and
- Department of Genetics, Yale University, New Haven, Connecticut, USA
| |
Collapse
|
18
|
Zuo Y, Li B, Gao M, Xiong R, He R, Li N, Geng Q. Novel insights and new therapeutic potentials for macrophages in pulmonary hypertension. Respir Res 2024; 25:147. [PMID: 38555425 PMCID: PMC10981837 DOI: 10.1186/s12931-024-02772-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 03/13/2024] [Indexed: 04/02/2024] Open
Abstract
Inflammation and immune processes underlie pulmonary hypertension progression. Two main different activated phenotypes of macrophages, classically activated M1 macrophages and alternatively activated M2 macrophages, are both involved in inflammatory processes related to pulmonary hypertension. Recent advances suggest that macrophages coordinate interactions among different proinflammatory and anti-inflammatory mediators, and other cellular components such as smooth muscle cells and fibroblasts. In this review, we summarize the current literature on the role of macrophages in the pathogenesis of pulmonary hypertension, including the origin of pulmonary macrophages and their response to triggers of pulmonary hypertension. We then discuss the interactions among macrophages, cytokines, and vascular adventitial fibroblasts in pulmonary hypertension, as well as the potential therapeutic benefits of macrophages in this disease. Identifying the critical role of macrophages in pulmonary hypertension will contribute to a comprehensive understanding of this pathophysiological abnormality, and may provide new perspectives for pulmonary hypertension management.
Collapse
Affiliation(s)
- Yifan Zuo
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Boyang Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Minglang Gao
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Rui Xiong
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Ruyuan He
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Ning Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
| |
Collapse
|
19
|
Osorio-Valencia S, Zhou B. Roles of Macrophages and Endothelial Cells and Their Crosstalk in Acute Lung Injury. Biomedicines 2024; 12:632. [PMID: 38540245 PMCID: PMC10968255 DOI: 10.3390/biomedicines12030632] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/08/2024] [Accepted: 03/10/2024] [Indexed: 11/11/2024] Open
Abstract
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), present life-threatening conditions characterized by inflammation and endothelial injury, leading to increased vascular permeability and lung edema. Key players in the pathogenesis and resolution of ALI are macrophages (Mφs) and endothelial cells (ECs). The crosstalk between these two cell types has emerged as a significant focus for potential therapeutic interventions in ALI. This review provides a brief overview of the roles of Mφs and ECs and their interplay in ALI/ARDS. Moreover, it highlights the significance of investigating perivascular macrophages (PVMs) and immunomodulatory endothelial cells (IMECs) as crucial participants in the Mφ-EC crosstalk. This sheds light on the pathogenesis of ALI and paves the way for innovative treatment approaches.
Collapse
Affiliation(s)
| | - Bisheng Zhou
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA;
| |
Collapse
|
20
|
Lin A, Brittan M, Baker AH, Dimmeler S, Fisher EA, Sluimer JC, Misra A. Clonal Expansion in Cardiovascular Pathology. JACC Basic Transl Sci 2024; 9:120-144. [PMID: 38362345 PMCID: PMC10864919 DOI: 10.1016/j.jacbts.2023.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/13/2023] [Accepted: 04/14/2023] [Indexed: 02/17/2024]
Abstract
Clonal expansion refers to the proliferation and selection of advantageous "clones" that are better suited for survival in a Darwinian manner. In recent years, we have greatly enhanced our understanding of cell clonality in the cardiovascular context. However, our knowledge of the underlying mechanisms behind this clonal selection is still severely limited. There is a transpiring pattern of clonal expansion of smooth muscle cells and endothelial cells-and, in some cases, macrophages-in numerous cardiovascular diseases irrespective of their differing microenvironments. These findings indirectly suggest the possible existence of stem-like vascular cells which are primed to respond during disease. Subsequent clones may undergo further phenotypic changes to adopt either protective or detrimental roles. By investigating these clone-forming vascular cells, we may be able to harness this inherent clonal nature for future therapeutic intervention. This review comprehensively discusses what is currently known about clonal expansion across the cardiovascular field. Comparisons of the clonal nature of vascular cells in atherosclerosis (including clonal hematopoiesis of indeterminate potential), pulmonary hypertension, aneurysm, blood vessel injury, ischemia- and tumor-induced angiogenesis, and cerebral cavernous malformations are evaluated. Finally, we discuss the potential clinical implications of these findings and propose that proper understanding and specific targeting of these clonal cells may provide unique therapeutic options for the treatment of these cardiovascular conditions.
Collapse
Affiliation(s)
- Alexander Lin
- Atherosclerosis and Vascular Remodeling Group, Heart Research Institute, Sydney, New South Wales, Australia
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, Sydney, New South Wales, Australia
| | - Mairi Brittan
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Andrew H. Baker
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
- CARIM School for Cardiovascular Sciences, Department of Pathology, Maastricht University Medical Center (MUMC), Maastricht, the Netherlands
| | - Stefanie Dimmeler
- Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt, Germany
- German Center for Cardiovascular Research (DZHK), partner site Frankfurt Rhine-Main, Berlin, Germany
- Cardiopulmonary Institute, Goethe University Frankfurt, Frankfurt, Germany
| | - Edward A. Fisher
- Department of Medicine/Division of Cardiology, New York University Grossman School of Medicine, New York, New York, USA
- Cardiovascular Research Center, New York University Grossman School of Medicine, New York, New York, USA
| | - Judith C. Sluimer
- Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
- CARIM School for Cardiovascular Sciences, Department of Pathology, Maastricht University Medical Center (MUMC), Maastricht, the Netherlands
| | - Ashish Misra
- Atherosclerosis and Vascular Remodeling Group, Heart Research Institute, Sydney, New South Wales, Australia
- Heart Research Institute, The University of Sydney, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| |
Collapse
|
21
|
Ji ZZ, Chan MKK, Chan ASW, Leung KT, Jiang X, To KF, Wu Y, Tang PMK. Tumour-associated macrophages: versatile players in the tumour microenvironment. Front Cell Dev Biol 2023; 11:1261749. [PMID: 37965573 PMCID: PMC10641386 DOI: 10.3389/fcell.2023.1261749] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 10/12/2023] [Indexed: 11/16/2023] Open
Abstract
Tumour-Associated Macrophages (TAMs) are one of the pivotal components of the tumour microenvironment. Their roles in the cancer immunity are complicated, both pro-tumour and anti-cancer activities are reported, including not only angiogenesis, extracellular matrix remodeling, immunosuppression, drug resistance but also phagocytosis and tumour regression. Interestingly, TAMs are highly dynamic and versatile in solid tumours. They show anti-cancer or pro-tumour activities, and interplay between the tumour microenvironment and cancer stem cells and under specific conditions. In addition to the classic M1/M2 phenotypes, a number of novel dedifferentiation phenomena of TAMs are discovered due to the advanced single-cell technology, e.g., macrophage-myofibroblast transition (MMT) and macrophage-neuron transition (MNT). More importantly, emerging information demonstrated the potential of TAMs on cancer immunotherapy, suggesting by the therapeutic efficiency of the checkpoint inhibitors and chimeric antigen receptor engineered cells based on macrophages. Here, we summarized the latest discoveries of TAMs from basic and translational research and discussed their clinical relevance and therapeutic potential for solid cancers.
Collapse
Affiliation(s)
- Zoey Zeyuan Ji
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Max Kam-Kwan Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Alex Siu-Wing Chan
- Department of Applied Social Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Kam-Tong Leung
- Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Xiaohua Jiang
- Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Yi Wu
- MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
| | - Patrick Ming-Kuen Tang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| |
Collapse
|
22
|
Pullamsetti SS, Sitapara R, Osterhout R, Weiss A, Carter LL, Zisman LS, Schermuly RT. Pharmacology and Rationale for Seralutinib in the Treatment of Pulmonary Arterial Hypertension. Int J Mol Sci 2023; 24:12653. [PMID: 37628831 PMCID: PMC10454154 DOI: 10.3390/ijms241612653] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/25/2023] [Accepted: 07/31/2023] [Indexed: 08/27/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The histologic hallmarks of PAH include plexiform and neointimal lesions of the pulmonary arterioles, which are composed of dysregulated, apoptosis-resistant endothelial cells and myofibroblasts. Platelet-derived growth factor receptors (PDGFR) α and β, colony stimulating factor 1 receptor (CSF1R), and mast/stem cell growth factor receptor kit (c-KIT) are closely related kinases that have been implicated in PAH progression. In addition, emerging data indicate significant crosstalk between PDGF signaling and the bone morphogenetic protein receptor type 2 (BMPR2)/transforming growth factor β (TGFβ) receptor axis. This review will discuss the importance of the PDGFR-CSF1R-c-KIT signaling network in PAH pathogenesis, present evidence that the inhibition of all three nodes in this kinase network is a potential therapeutic approach for PAH, and highlight the therapeutic potential of seralutinib, currently in development for PAH, which targets these pathways.
Collapse
Affiliation(s)
- Soni Savai Pullamsetti
- Lung Vascular Epigenetics, Center for Infection and Genomics of the Lung (CIGL), Justus-Liebig-Universität Gießen, Aulweg 132, 35392 Giessen, Germany;
| | | | | | - Astrid Weiss
- UGMLC Pulmonale Pharmakotherapie, Biomedizinisches Forschungszentrum Seltersberg (BFS), Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392 Giessen, Germany;
| | | | | | - Ralph Theo Schermuly
- Department of Internal Medicine, Justus-Liebig-University Giessen, Aulweg 130, 35392 Giessen, Germany
| |
Collapse
|
23
|
Balistrieri A, Makino A, Yuan JXJ. Pathophysiology and pathogenic mechanisms of pulmonary hypertension: role of membrane receptors, ion channels, and Ca 2+ signaling. Physiol Rev 2023; 103:1827-1897. [PMID: 36422993 PMCID: PMC10110735 DOI: 10.1152/physrev.00030.2021] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/11/2022] [Accepted: 11/19/2022] [Indexed: 11/25/2022] Open
Abstract
The pulmonary circulation is a low-resistance, low-pressure, and high-compliance system that allows the lungs to receive the entire cardiac output. Pulmonary arterial pressure is a function of cardiac output and pulmonary vascular resistance, and pulmonary vascular resistance is inversely proportional to the fourth power of the intraluminal radius of the pulmonary artery. Therefore, a very small decrease of the pulmonary vascular lumen diameter results in a significant increase in pulmonary vascular resistance and pulmonary arterial pressure. Pulmonary arterial hypertension is a fatal and progressive disease with poor prognosis. Regardless of the initial pathogenic triggers, sustained pulmonary vasoconstriction, concentric vascular remodeling, occlusive intimal lesions, in situ thrombosis, and vascular wall stiffening are the major and direct causes for elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension and other forms of precapillary pulmonary hypertension. In this review, we aim to discuss the basic principles and physiological mechanisms involved in the regulation of lung vascular hemodynamics and pulmonary vascular function, the changes in the pulmonary vasculature that contribute to the increased vascular resistance and arterial pressure, and the pathogenic mechanisms involved in the development and progression of pulmonary hypertension. We focus on reviewing the pathogenic roles of membrane receptors, ion channels, and intracellular Ca2+ signaling in pulmonary vascular smooth muscle cells in the development and progression of pulmonary hypertension.
Collapse
Affiliation(s)
- Angela Balistrieri
- Section of Physiology, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
- Harvard University, Cambridge, Massachusetts
| | - Ayako Makino
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Jason X-J Yuan
- Section of Physiology, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| |
Collapse
|
24
|
Ye Y, Xu Q, Wuren T. Inflammation and immunity in the pathogenesis of hypoxic pulmonary hypertension. Front Immunol 2023; 14:1162556. [PMID: 37215139 PMCID: PMC10196112 DOI: 10.3389/fimmu.2023.1162556] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 04/25/2023] [Indexed: 05/24/2023] Open
Abstract
Hypoxic pulmonary hypertension (HPH) is a complicated vascular disorder characterized by diverse mechanisms that lead to elevated blood pressure in pulmonary circulation. Recent evidence indicates that HPH is not simply a pathological syndrome but is instead a complex lesion of cellular metabolism, inflammation, and proliferation driven by the reprogramming of gene expression patterns. One of the key mechanisms underlying HPH is hypoxia, which drives immune/inflammation to mediate complex vascular homeostasis that collaboratively controls vascular remodeling in the lungs. This is caused by the prolonged infiltration of immune cells and an increase in several pro-inflammatory factors, which ultimately leads to immune dysregulation. Hypoxia has been associated with metabolic reprogramming, immunological dysregulation, and adverse pulmonary vascular remodeling in preclinical studies. Many animal models have been developed to mimic HPH; however, many of them do not accurately represent the human disease state and may not be suitable for testing new therapeutic strategies. The scientific understanding of HPH is rapidly evolving, and recent efforts have focused on understanding the complex interplay among hypoxia, inflammation, and cellular metabolism in the development of this disease. Through continued research and the development of more sophisticated animal models, it is hoped that we will be able to gain a deeper understanding of the underlying mechanisms of HPH and implement more effective therapies for this debilitating disease.
Collapse
Affiliation(s)
- Yi Ye
- Research Center for High Altitude Medicine, Qinghai University, Xining, China
- High-Altitude Medicine Key Laboratory of the Ministry of Education, Xining, China
- Qinghai Provincial Key Laboratory for Application of High-Altitude Medicine, Xining, China
- Qinghai-Utah Key Laboratory of High-Altitude Medicine, Xining, China
| | - Qiying Xu
- Research Center for High Altitude Medicine, Qinghai University, Xining, China
- High-Altitude Medicine Key Laboratory of the Ministry of Education, Xining, China
- Qinghai Provincial Key Laboratory for Application of High-Altitude Medicine, Xining, China
- Qinghai-Utah Key Laboratory of High-Altitude Medicine, Xining, China
| | - Tana Wuren
- Research Center for High Altitude Medicine, Qinghai University, Xining, China
- High-Altitude Medicine Key Laboratory of the Ministry of Education, Xining, China
- Qinghai Provincial Key Laboratory for Application of High-Altitude Medicine, Xining, China
- Qinghai-Utah Key Laboratory of High-Altitude Medicine, Xining, China
| |
Collapse
|
25
|
Hu L, Yu Y, Shen Y, Huang H, Lin D, Wang K, Yu Y, Li K, Cao Y, Wang Q, Sun X, Qiu Z, Wei D, Shen B, Chen J, Fulton D, Ji Y, Wang J, Chen F. Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages. Redox Biol 2023; 61:102638. [PMID: 36801705 PMCID: PMC9975317 DOI: 10.1016/j.redox.2023.102638] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/04/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Pulmonary hypertension (PH) is a devastating disease characterized by irreversible pulmonary vascular remodeling (PVR) that causes right ventricular failure and death. The early alternative activation of macrophages is a critical event in the development of PVR and PH, but the underlying mechanisms remain elusive. Previously we have shown that N6-methyladenosine (m6A) modifications of RNA contribute to phenotypic switching of pulmonary artery smooth muscle cells and PH. In the current study, we identify Ythdf2, an m6A reader, as an important regulator of pulmonary inflammation and redox regulation in PH. In a mouse model of PH, the protein expression of Ythdf2 was increased in alveolar macrophages (AMs) during the early stages of hypoxia. Mice with a myeloid specific knockout of Ythdf2 (Ythdf2Lyz2 Cre) were protected from PH with attenuated right ventricular hypertrophy and PVR compared to control mice and this was accompanied by decreased macrophage polarization and oxidative stress. In the absence of Ythdf2, heme oxygenase 1 (Hmox1) mRNA and protein expression were significantly elevated in hypoxic AMs. Mechanistically, Ythdf2 promoted the degradation of Hmox1 mRNA in a m6A dependent manner. Furthermore, an inhibitor of Hmox1 promoted macrophage alternative activation, and reversed the protection from PH seen in Ythdf2Lyz2 Cre mice under hypoxic exposure. Together, our data reveal a novel mechanism linking m6A RNA modification with changes in macrophage phenotype, inflammation and oxidative stress in PH, and identify Hmox1 as a downstream target of Ythdf2, suggesting that Ythdf2 may be a therapeutic target in PH.
Collapse
Affiliation(s)
- Li Hu
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, China; Gusu School, Nanjing Medical University, Suzhou, China
| | - Yanfang Yu
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
| | - Yueyao Shen
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
| | - Huijie Huang
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
| | - Donghai Lin
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
| | - Kang Wang
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
| | - Youjia Yu
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
| | - Kai Li
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
| | - Yue Cao
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
| | - Qiang Wang
- Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoxuan Sun
- Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhibing Qiu
- Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Dong Wei
- Wuxi Lung Transplantation Center, Wuxi People's Hospital Affiliated with Nanjing Medical University, Wuxi, China
| | - Bin Shen
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Jingyu Chen
- Wuxi Lung Transplantation Center, Wuxi People's Hospital Affiliated with Nanjing Medical University, Wuxi, China
| | - David Fulton
- Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Yong Ji
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Jie Wang
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, China.
| | - Feng Chen
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, China; Gusu School, Nanjing Medical University, Suzhou, China; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.
| |
Collapse
|
26
|
Gallardo-Vara E, Ntokou A, Dave JM, Jovin DG, Saddouk FZ, Greif DM. Vascular pathobiology of pulmonary hypertension. J Heart Lung Transplant 2023; 42:544-552. [PMID: 36604291 PMCID: PMC10121751 DOI: 10.1016/j.healun.2022.12.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 10/31/2022] [Accepted: 12/10/2022] [Indexed: 12/24/2022] Open
Abstract
Pulmonary hypertension (PH), increased blood pressure in the pulmonary arteries, is a morbid and lethal disease. PH is classified into several groups based on etiology, but pathological remodeling of the pulmonary vasculature is a common feature. Endothelial cell dysfunction and excess smooth muscle cell proliferation and migration are central to the vascular pathogenesis. In addition, other cell types, including fibroblasts, pericytes, inflammatory cells and platelets contribute as well. Herein, we briefly note most of the main cell types active in PH and for each cell type, highlight select signaling pathway(s) highly implicated in that cell type in this disease. Among others, the role of hypoxia-inducible factors, growth factors (e.g., vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor-β and bone morphogenetic protein), vasoactive molecules, NOTCH3, Kruppel-like factor 4 and forkhead box proteins are discussed. Additionally, deregulated processes of endothelial-to-mesenchymal transition, extracellular matrix remodeling and intercellular crosstalk are noted. This brief review touches upon select critical facets of PH pathobiology and aims to incite further investigation that will result in discoveries with much-needed clinical impact for this devastating disease.
Collapse
Affiliation(s)
- Eunate Gallardo-Vara
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, New Haven, Connecticut; Department of Genetics, Yale University, New Haven, Connecticut
| | - Aglaia Ntokou
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, New Haven, Connecticut; Department of Genetics, Yale University, New Haven, Connecticut
| | - Jui M Dave
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, New Haven, Connecticut; Department of Genetics, Yale University, New Haven, Connecticut
| | - Daniel G Jovin
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, New Haven, Connecticut; Department of Genetics, Yale University, New Haven, Connecticut
| | - Fatima Z Saddouk
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, New Haven, Connecticut; Department of Genetics, Yale University, New Haven, Connecticut
| | - Daniel M Greif
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, New Haven, Connecticut; Department of Genetics, Yale University, New Haven, Connecticut.
| |
Collapse
|
27
|
Kuramoto K, Ogawa A, Kiyama K, Matsubara H, Ohno Y, Fuchikami C, Hayashi K, Kosugi K, Kuwano K. Antiproliferative effect of selexipag active metabolite MRE-269 on pulmonary arterial smooth muscle cells from patients with chronic thromboembolic pulmonary hypertension. Pulm Circ 2023; 13:e12231. [PMID: 37180827 PMCID: PMC10173849 DOI: 10.1002/pul2.12231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 04/13/2023] [Accepted: 04/15/2023] [Indexed: 05/16/2023] Open
Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is a group 4 pulmonary hypertension (PH) characterized by nonresolving thromboembolism in the central pulmonary artery and vascular occlusion in the proximal and distal pulmonary artery. Medical therapy is chosen for patients who are ineligible for pulmonary endarterectomy or balloon pulmonary angioplasty or who have symptomatic residual PH after surgery or intervention. Selexipag, an oral prostacyclin receptor agonist and potent vasodilator, was approved for CTEPH in Japan in 2021. To evaluate the pharmacological effect of selexipag on vascular occlusion in CTEPH, we examined how its active metabolite MRE-269 affects platelet-derived growth factor-stimulated pulmonary arterial smooth muscle cells (PASMCs) from CTEPH patients. MRE-269 showed a more potent antiproliferative effect on PASMCs from CTEPH patients than on those from normal subjects. DNA-binding protein inhibitor (ID) genes ID1 and ID3 were found by RNA sequencing and real-time quantitative polymerase chain reaction to be expressed at lower levels in PASMCs from CTEPH patients than in those from normal subjects and were upregulated by MRE-269 treatment. ID1 and ID3 upregulation by MRE-269 was blocked by co-incubation with a prostacyclin receptor antagonist, and ID1 knockdown by small interfering RNA transfection attenuated the antiproliferative effect of MRE-269. ID signaling may be involved in the antiproliferative effect of MRE-269 on PASMCs. This is the first study to demonstrate the pharmacological effects on PASMCs from CTEPH patients of a drug approved for the treatment of CTEPH. Both the vasodilatory and the antiproliferative effect of MRE-269 may contribute to the efficacy of selexipag in CTEPH.
Collapse
Affiliation(s)
- Kazuya Kuramoto
- Discovery Research LaboratoriesNippon Shinyaku Co., LtdKyotoJapan
| | - Aiko Ogawa
- Department of Clinical ScienceNational Hospital Organization Okayama Medical CenterOkayamaJapan
| | - Kazuko Kiyama
- Department of Clinical ScienceNational Hospital Organization Okayama Medical CenterOkayamaJapan
| | - Hiromi Matsubara
- Department of CardiologyNational Hospital Organization Okayama Medical CenterOkayamaJapan
| | - Yuji Ohno
- Discovery Research LaboratoriesNippon Shinyaku Co., LtdKyotoJapan
| | - Chiaki Fuchikami
- Discovery Research LaboratoriesNippon Shinyaku Co., LtdKyotoJapan
| | - Kyota Hayashi
- Discovery Research LaboratoriesNippon Shinyaku Co., LtdKyotoJapan
| | - Keiji Kosugi
- Discovery Research LaboratoriesNippon Shinyaku Co., LtdKyotoJapan
| | - Keiichi Kuwano
- Discovery Research LaboratoriesNippon Shinyaku Co., LtdKyotoJapan
| |
Collapse
|
28
|
Kabir I, Zhang X, Dave JM, Chakraborty R, Qu R, Chandran RR, Ntokou A, Gallardo-Vara E, Aryal B, Rotllan N, Garcia-Milian R, Hwa J, Kluger Y, Martin KA, Fernández-Hernando C, Greif DM. The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques. NATURE AGING 2023; 3:64-81. [PMID: 36743663 PMCID: PMC9894379 DOI: 10.1038/s43587-022-00342-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cell (SMC) progenitors clonally expand giving rise to up to ~70% of atherosclerotic plaque cells; however, the effect of age on SMC clonality is not known. Our results indicate that aged bone marrow (BM)-derived cells non-cell autonomously induce SMC polyclonality and worsen atherosclerosis. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin β3 resulting in increased tumor necrosis factor [TNF]-α signaling. TNFα signals through TNF receptor 1 on SMCs to promote proliferation and induces recruitment and expansion of multiple SMC progenitors into the atherosclerotic plaque. Notably, integrin β3 overexpression in aged BM preserves dominance of the lineage of a single SMC progenitor and attenuates plaque burden. Our results demonstrate a molecular mechanism of aged macrophage-induced SMC polyclonality and atherogenesis and suggest novel therapeutic strategies.
Collapse
Affiliation(s)
- Inamul Kabir
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, CT 06511, USA
- Department of Genetics, Yale University, New Haven, CT 06511, USA
- To whom correspondence should be addressed: or , 203-737-2040 (phone), 203-737-6118 (FAX)
| | - Xinbo Zhang
- Department of Comparative Medicine, Yale University, New Haven, CT 06511, USA
| | - Jui M. Dave
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, CT 06511, USA
- Department of Genetics, Yale University, New Haven, CT 06511, USA
| | - Raja Chakraborty
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, CT 06511, USA
| | - Rihao Qu
- Department of Pathology, Yale University, New Haven, CT 06511, USA
| | - Rachana R. Chandran
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, CT 06511, USA
- Department of Genetics, Yale University, New Haven, CT 06511, USA
| | - Aglaia Ntokou
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, CT 06511, USA
- Department of Genetics, Yale University, New Haven, CT 06511, USA
| | - Eunate Gallardo-Vara
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, CT 06511, USA
- Department of Genetics, Yale University, New Haven, CT 06511, USA
| | - Binod Aryal
- Department of Comparative Medicine, Yale University, New Haven, CT 06511, USA
| | - Noemi Rotllan
- Department of Comparative Medicine, Yale University, New Haven, CT 06511, USA
| | - Rolando Garcia-Milian
- Department of Bioinformatics Support Program, Yale University, New Haven, CT 06511, USA
| | - John Hwa
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, CT 06511, USA
| | - Yuval Kluger
- Department of Pathology, Yale University, New Haven, CT 06511, USA
| | - Kathleen A. Martin
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, CT 06511, USA
| | - Carlos Fernández-Hernando
- Department of Comparative Medicine, Yale University, New Haven, CT 06511, USA
- Department of Pathology, Yale University, New Haven, CT 06511, USA
| | - Daniel M. Greif
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, CT 06511, USA
- Department of Genetics, Yale University, New Haven, CT 06511, USA
- To whom correspondence should be addressed: or , 203-737-2040 (phone), 203-737-6118 (FAX)
| |
Collapse
|
29
|
Zhang MQ, Wang CC, Pang XB, Shi JZ, Li HR, Xie XM, Wang Z, Zhang HD, Zhou YF, Chen JW, Han ZY, Zhao LL, He YY. Role of macrophages in pulmonary arterial hypertension. Front Immunol 2023; 14:1152881. [PMID: 37153557 PMCID: PMC10154553 DOI: 10.3389/fimmu.2023.1152881] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 03/27/2023] [Indexed: 05/09/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary vascular disease characterized by progressive pulmonary artery pressure elevation, increased pulmonary vascular resistance and ultimately right heart failure. Studies have demonstrated the involvement of multiple immune cells in the development of PAH in patients with PAH and in experimental PAH. Among them, macrophages, as the predominant inflammatory cells infiltrating around PAH lesions, play a crucial role in exacerbating pulmonary vascular remodeling in PAH. Macrophages are generally polarized into (classic) M1 and (alternative) M2 phenotypes, they accelerate the process of PAH by secreting various chemokines and growth factors (CX3CR1, PDGF). In this review we summarize the mechanisms of immune cell action in PAH, as well as the key factors that regulate the polarization of macrophages in different directions and their functional changes after polarization. We also summarize the effects of different microenvironments on macrophages in PAH. The insight into the interactions between macrophages and other cells, chemokines and growth factors may provide important clues for the development of new, safe and effective immune-targeted therapies for PAH.
Collapse
Affiliation(s)
- Meng-Qi Zhang
- School of Pharmacy, Henan University, Kaifeng, Henan, China
| | - Chen-Chen Wang
- School of Pharmacy, Henan University, Kaifeng, Henan, China
| | - Xiao-Bin Pang
- School of Pharmacy, Henan University, Kaifeng, Henan, China
| | - Jun-Zhuo Shi
- School of Pharmacy, Henan University, Kaifeng, Henan, China
| | - Hao-Ran Li
- School of Pharmacy, Henan University, Kaifeng, Henan, China
| | - Xin-Mei Xie
- School of Pharmacy, Henan University, Kaifeng, Henan, China
| | - Zhe Wang
- School of Pharmacy, Henan University, Kaifeng, Henan, China
| | - Hong-Da Zhang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yun-Feng Zhou
- School of Pharmacy, Henan University, Kaifeng, Henan, China
| | - Ji-Wang Chen
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Zhi-Yan Han
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Yang-Yang He, ; Lu-Ling Zhao, ; Zhi-Yan Han,
| | - Lu-Ling Zhao
- School of Pharmacy, Henan University, Kaifeng, Henan, China
- *Correspondence: Yang-Yang He, ; Lu-Ling Zhao, ; Zhi-Yan Han,
| | - Yang-Yang He
- School of Pharmacy, Henan University, Kaifeng, Henan, China
- *Correspondence: Yang-Yang He, ; Lu-Ling Zhao, ; Zhi-Yan Han,
| |
Collapse
|
30
|
Zhou W, Liu K, Zeng L, He J, Gao X, Gu X, Chen X, Jing Li J, Wang M, Wu D, Cai Z, Claesson-Welsh L, Ju R, Wang J, Zhang F, Chen Y. Targeting VEGF-A/VEGFR2 Y949 Signaling-Mediated Vascular Permeability Alleviates Hypoxic Pulmonary Hypertension. Circulation 2022; 146:1855-1881. [PMID: 36384284 DOI: 10.1161/circulationaha.122.061900] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND Pulmonary hypertension (PH) is associated with increased expression of VEGF-A (vascular endothelial growth factor A) and its receptor, VEGFR2 (vascular endothelial growth factor 2), but whether and how activation of VEGF-A signal participates in the pathogenesis of PH is unclear. METHODS VEGF-A/VEGFR2 signal activation and VEGFR2 Y949-dependent vascular leak were investigated in lung samples from patients with PH and mice exposed to hypoxia. To study their mechanistic roles in hypoxic PH, we examined right ventricle systolic pressure, right ventricular hypertrophy, and pulmonary vasculopathy in mutant mice carrying knock-in of phenylalanine that replaced the tyrosine at residual 949 of VEGFR2 (Vefgr2Y949F) and mice with conditional endothelial deletion of Vegfr2 after chronic hypoxia exposure. RESULTS We show that PH leads to excessive pulmonary vascular leak in both patients and hypoxic mice, and this is because of an overactivated VEGF-A/VEGFR2 Y949 signaling axis. In the context of hypoxic PH, activation of Yes1 and c-Src and subsequent VE-cadherin phosphorylation in endothelial cells are involved in VEGFR2 Y949-induced vascular permeability. Abolishing VEGFR2 Y949 signaling by Vefgr2Y949F point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure, thereby leading to alleviated PH manifestations, including muscularization of distal pulmonary arterioles, elevated right ventricle systolic pressure, and right ventricular hypertrophy. It is important that we found that VEGFR2 Y949 signaling in myeloid cells including macrophages was trivial and dispensable for hypoxia-induced vascular abnormalities and PH. In contrast with selective blockage of VEGFR2 Y949 signaling, disruption of the entire VEGFR2 signaling by conditional endothelial deletion of Vegfr2 promotes the development of PH. CONCLUSIONS Our results support the notion that VEGF-A/VEGFR2 Y949-dependent vascular permeability is an important determinant in the pathogenesis of PH and might serve as an attractive therapeutic target pathway for this disease.
Collapse
Affiliation(s)
- Weibin Zhou
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China (W.Z., J.H., M.W., D.W., J.W., Y.C.).,State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China (W.Z., K.L., L.Z., X. Gao, X. Gu, X.C., J.J.L., R.J., F.Z.).,Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (W.Z., J.H., J.W., Y.C.)
| | - Keli Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China (W.Z., K.L., L.Z., X. Gao, X. Gu, X.C., J.J.L., R.J., F.Z.)
| | - Lei Zeng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China (W.Z., K.L., L.Z., X. Gao, X. Gu, X.C., J.J.L., R.J., F.Z.)
| | - Jiaqi He
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China (W.Z., J.H., M.W., D.W., J.W., Y.C.).,Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (W.Z., J.H., J.W., Y.C.)
| | - Xinbo Gao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China (W.Z., K.L., L.Z., X. Gao, X. Gu, X.C., J.J.L., R.J., F.Z.)
| | - Xinyu Gu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China (W.Z., K.L., L.Z., X. Gao, X. Gu, X.C., J.J.L., R.J., F.Z.)
| | - Xun Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China (W.Z., K.L., L.Z., X. Gao, X. Gu, X.C., J.J.L., R.J., F.Z.)
| | - Jing Jing Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China (W.Z., K.L., L.Z., X. Gao, X. Gu, X.C., J.J.L., R.J., F.Z.)
| | - Minghui Wang
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China (W.Z., J.H., M.W., D.W., J.W., Y.C.)
| | - Duoguang Wu
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China (W.Z., J.H., M.W., D.W., J.W., Y.C.)
| | - Zhixiong Cai
- Department of Cardiology, Shantou Central Hospital, China (Z.C.)
| | - Lena Claesson-Welsh
- Rudbeck, SciLifeLab and Beijer Laboratories, Department of Immunology, Genetics and Pathology, Uppsala University, Sweden (L.C.-W.)
| | - Rong Ju
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China (W.Z., K.L., L.Z., X. Gao, X. Gu, X.C., J.J.L., R.J., F.Z.)
| | - Jingfeng Wang
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China (W.Z., J.H., M.W., D.W., J.W., Y.C.).,Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (W.Z., J.H., J.W., Y.C.)
| | - Feng Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China (W.Z., K.L., L.Z., X. Gao, X. Gu, X.C., J.J.L., R.J., F.Z.)
| | - Yangxin Chen
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China (W.Z., J.H., M.W., D.W., J.W., Y.C.).,Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (W.Z., J.H., J.W., Y.C.)
| |
Collapse
|
31
|
Yao H, Tang G. Macrophages in intestinal fibrosis and regression. Cell Immunol 2022; 381:104614. [PMID: 36182587 DOI: 10.1016/j.cellimm.2022.104614] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/14/2022] [Accepted: 09/20/2022] [Indexed: 11/03/2022]
Abstract
Intestinal macrophages are heterogenous cell populations with different developmental ontogeny and tissue anatomy. The concerted actions of intestinal macrophage subsets are critical to maintaining tissue homeostasis. However, the dysregulation of macrophages following tissue injury or chronic inflammation could also lead to intestinal fibrosis, with few treatment options in the clinic. In this review, we will characterize the features of intestinal macrophages in light of the latest advances in lineage tracing and single-cell sequencing technology. The roles of macrophages in distinct stages of intestinal fibrosis would be also elaborated. Finally, based on the reciprocal interaction between macrophages and intestinal fibrosis, we will propose the potential macrophage targeting anti-intestinal fibrosis therapies.
Collapse
Affiliation(s)
- Hui Yao
- Department of Oral Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China; National Center for Stomatology, Shanghai 200011, China; National Clinical Research Center for Oral Diseases, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai 200011, China
| | - Guoyao Tang
- Department of Oral Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China; National Center for Stomatology, Shanghai 200011, China; National Clinical Research Center for Oral Diseases, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.
| |
Collapse
|
32
|
Bratoiu I, Burlui AM, Cardoneanu A, Macovei LA, Richter P, Rusu-Zota G, Rezus C, Badescu MC, Szalontay A, Rezus E. The Involvement of Smooth Muscle, Striated Muscle, and the Myocardium in Scleroderma: A Review. Int J Mol Sci 2022; 23:ijms231912011. [PMID: 36233313 PMCID: PMC9569846 DOI: 10.3390/ijms231912011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/24/2022] [Accepted: 10/07/2022] [Indexed: 11/09/2022] Open
Abstract
Systemic sclerosis (SSc) is a complex autoimmune disease characterized by heterogeneous changes involving numerous organs and systems. The currently available data indicate that muscle injury (both smooth and striated muscles) is widespread and leads to significant morbidity, either directly or indirectly. From the consequences of smooth muscle involvement in the tunica media of blood vessels or at the level of the digestive tract, to skeletal myopathy (which may be interpreted strictly in the context of SSc, or as an overlap with idiopathic inflammatory myopathies), muscular injury in scleroderma translates to a number of notable clinical manifestations. Heart involvement in SSc is heterogenous depending on the definition used in the various studies. The majority of SSc patients experience a silent form of cardiac disease. The present review summarizes certain important features of myocardial, as well as smooth and skeletal muscle involvement in SSc. Further research is needed to fully describe and understand the pathogenic pathways and the implications of muscle involvement in scleroderma.
Collapse
Affiliation(s)
- Ioana Bratoiu
- Department of Rheumatology and Physiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania
| | - Alexandra Maria Burlui
- Department of Rheumatology and Physiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania
- Correspondence: (A.M.B.); (C.R.)
| | - Anca Cardoneanu
- Department of Rheumatology and Physiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania
| | - Luana Andreea Macovei
- Department of Rheumatology and Physiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania
| | - Patricia Richter
- Department of Rheumatology and Physiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania
| | - Gabriela Rusu-Zota
- Department of Pharmacology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania
| | - Ciprian Rezus
- Department of Internal Medicine, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
- Correspondence: (A.M.B.); (C.R.)
| | - Minerva Codruta Badescu
- Department of Internal Medicine, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Andreea Szalontay
- Department of Psychiatry, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania
| | - Elena Rezus
- Department of Rheumatology and Physiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania
| |
Collapse
|
33
|
Remes A, Körbelin J, Arnold C, Rohwedder C, Heckmann MB, Mairbauerl H, Frank D, Korff T, Frey N, Trepel M, Müller OJ. AAV-mediated gene transfer of inducible nitric oxide synthase (iNOS) to an animal model of pulmonary hypertension. Hum Gene Ther 2022; 33:959-967. [PMID: 35850528 DOI: 10.1089/hum.2021.230] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Pulmonary hypertension (PH) is characterized by progressive obstruction of pulmonary arteries due to inflammatory processes, cellular proliferation, and extracellular matrix deposition and vasoconstriction. As treatment options are limited, we studied gene transfer of an inducible nitric oxide synthase (iNOS) using adeno-associated virus (AAV) vectors specifically targeted to endothelial cells of pulmonary vessels in a murine model of PH. Adult mice were intravenously injected with AAV vectors expressing iNOS. Mice were subjected to hypoxia for three weeks and sacrificed afterwards. We found elevated levels of iNOS both in lung tissue and pulmonary endothelial cells in hypoxic controls which could be further increased by AAV-mediated iNOS gene transfer. This additional increase in iNOS was associated with decreased wall thickness of pulmonary vessels, less macrophage infiltration, and reduced molecular markers of fibrosis. Taken together, using a tissue-targeted approach, we show that AAV-mediated iNOS overexpression in endothelial cells of the pulmonary vasculature significantly decreases vascular remodeling in a murine model of PH, suggesting upregulation of iNOS as promising target for treatment of PH.
Collapse
Affiliation(s)
- Anca Remes
- Department of Internal Medicine III, University of Kiel, and German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Germany, Kiel, Germany;
| | - Jakob Körbelin
- University Medical Center Hamburg-Eppendorf, Department of Oncology, Hematology and Bone Marrow Transplantation, Martinistr. 52, Division of Pneumology, Hamburg, Germany, 20246;
| | - Caroline Arnold
- Institute of Physiology and Pathophysiology, Heidelberg University, Germany, Heidelberg, Germany;
| | - Carolin Rohwedder
- Internal Medicine III, University Hospital Heidelberg, Germany, and German Centre for Cardiovascular Research, Partner Site Heidelberg/Mannheim, Heidelberg, Germany;
| | - Markus Benjamin Heckmann
- Internal Medicine III, University Hospital Heidelberg, Germany, and German Centre for Cardiovascular Research, Partner Site Heidelberg/Mannheim, Heidelberg, Germany;
| | - Heimo Mairbauerl
- Medical Clinic VII, Heidelberg University, Germany and Translational Lung Research Center, part of the German Center for Lung Research (DZL), University of Heidelberg, Germany, Heidelberg, Germany;
| | - Derk Frank
- Department of Internal Medicine III, University of Kiel, and German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Germany, Kiel, Germany;
| | - Thomas Korff
- Institute of Physiology and Pathophysiology, Heidelberg University, Germany, Heidelberg, Germany;
| | - Norbert Frey
- Internal Medicine III, University Hospital Heidelberg, Germany, and German Centre for Cardiovascular Research, Partner Site Heidelberg/Mannheim, Heidelberg, Germany;
| | - Martin Trepel
- Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf Germany, Hamburg, Germany.,Department of Hematology and Oncology, University Medical Center Augsburg, Germany, Ausburg, Germany;
| | - Oliver J Müller
- Department of Internal Medicine III, University of Kiel, and German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Germany, Kiel, Germany;
| |
Collapse
|
34
|
Aldehyde Dehydrogenase 2 (ALDH2) Elicits Protection against Pulmonary Hypertension via Inhibition of ERK1/2-Mediated Autophagy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2555476. [PMID: 35770049 PMCID: PMC9236760 DOI: 10.1155/2022/2555476] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 05/06/2022] [Accepted: 05/30/2022] [Indexed: 11/18/2022]
Abstract
Pulmonary hypertension (PH) is caused by chronic hypoxia that induces the migration and proliferation of pulmonary arterial smooth muscle cells (PASMCs), eventually resulting in right heart failure. PH has been related to aberrant autophagy; however, the hidden mechanisms are still unclear. Approximately 40% East Asians, equivalent to 8% of the universal population, carry a mutation in Aldehyde dehydrogenase 2 (ALDH2), which leads to the aggregation of noxious reactive aldehydes and increases the propensity of several diseases. Therefore, we explored the potential aspect of ALDH2 in autophagy associated with PH. In vitro mechanistic studies were conducted in human PASMCs (HPASMCs) after lentiviral ALDH2 knockdown and treatment with platelet-derived growth factor-BB (PDGF-BB). PH was induced in wild-type (WT) and ALDH2-knockout (ALDH2−/−) mice using vascular endothelial growth factor receptor inhibitor SU5416 under hypoxic conditions (HySU). Right ventricular function was assessed using echocardiography and invasive hemodynamic monitoring. Histological and immunohistochemical analyses were performed to evaluate pulmonary vascular remodeling. EdU, transwell, and wound healing assays were used to evaluate HPASMC migration and proliferation, and electron microscopy and immunohistochemical and immunoblot assays were performed to assess autophagy. The findings demonstrated that ALDH2 deficiency exacerbated right ventricular pressure, hypertrophy, fibrosis, and right heart failure resulting from HySU-induced PH. ALDH2−/− mice exhibited increased pulmonary artery muscularization and 4-hydroxynonenal (4-HNE) levels in lung tissues. ALDH2 knockdown increased PDGF-BB-induced PASMC migration and proliferation and 4-HNE accumulation in vitro. Additionally, ALDH2 deficiency increased the number of autophagosomes and autophagic lysosomes together with autophagic flux and ERK1/2-Beclin-1 activity in lung tissues and PASMCs, indicating enhanced autophagy. In conclusion, the study shows that ALDH2 has a protective role against the migration and proliferation of PASMCs and PH, possibly by regulating autophagy through the ERK1/2-Beclin-1 pathway.
Collapse
|
35
|
Yoshida T, Nagaoka T, Nagata Y, Suzuki Y, Tsutsumi T, Kuriyama S, Watanabe J, Togo S, Takahashi F, Matsushita M, Joki Y, Konishi H, Nunomura S, Izuhara K, Conway SJ, Takahashi K. Periostin-related progression of different types of experimental pulmonary hypertension: A role for M2 macrophage and FGF-2 signalling. Respirology 2022; 27:529-538. [PMID: 35318760 PMCID: PMC9313806 DOI: 10.1111/resp.14249] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 01/29/2022] [Accepted: 03/08/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND AND OBJECTIVE Remodelling of pulmonary arteries (PA) contributes to the progression of pulmonary hypertension (PH). Periostin, a matricellular protein, has been reported to be involved in the development of PH. We examined the role of periostin in the pathogenesis of PH using different types of experimental PH. METHODS PH was induced by vascular endothelial growth factor receptor antagonist (Sugen5416) plus hypoxic exposure (SuHx) and venous injection of monocrotaline-pyrrole (MCT-P) in wild-type (WT) and periostin-/- mice. Pulmonary haemodynamics, PA remodelling, expression of chemokines and fibroblast growth factor (FGF)-2, accumulation of macrophages to small PA and the right ventricle (RV) were examined in PH-induced WT and periostin-/- mice. Additionally, the role of periostin in the migration of macrophages, human PA smooth muscle (HPASMCs) and endothelial cells (HPMVECs) was investigated. RESULTS In PH induced by SuHx and MCT-P, PH and accumulation of M2 macrophage to small PA were attenuated in periostin-/- mice. PA remodelling post-SuHx treatment was also mild in periostin-/- mice compared to WT mice. Expression of macrophage-associated chemokines and FGF-2 in lung tissue, and accumulation of CD68-positive cells in the RV were less in SuHx periostin-/- than in SuHx WT mice. Periostin secretion in HPASMCs and HPMVECs was enhanced by transforming growth factor-β. Periostin also augmented macrophage, HPASMCs and HPMVECs migration. Separately, serum periostin levels were significantly elevated in patients with PH compared to healthy controls. CONCLUSION Periostin is involved in the development of different types of experimental PH, and may also contribute to the pathogenesis of human PH.
Collapse
Affiliation(s)
- Takashi Yoshida
- Department of Respiratory MedicineJuntendo University Faculty of Medicine and Graduate School of MedicineTokyoJapan
| | - Tetsutaro Nagaoka
- Department of Respiratory MedicineJuntendo University Faculty of Medicine and Graduate School of MedicineTokyoJapan
| | - Yuichi Nagata
- Department of Respiratory MedicineJuntendo University Faculty of Medicine and Graduate School of MedicineTokyoJapan
| | - Yoshifumi Suzuki
- Department of Respiratory MedicineJuntendo University Faculty of Medicine and Graduate School of MedicineTokyoJapan
| | - Takeo Tsutsumi
- Department of Respiratory MedicineJuntendo University Faculty of Medicine and Graduate School of MedicineTokyoJapan
| | - Sachiko Kuriyama
- Department of Respiratory MedicineJuntendo University Faculty of Medicine and Graduate School of MedicineTokyoJapan
| | - Junko Watanabe
- Department of Respiratory MedicineJuntendo University Faculty of Medicine and Graduate School of MedicineTokyoJapan
| | - Shinsaku Togo
- Department of Respiratory MedicineJuntendo University Faculty of Medicine and Graduate School of MedicineTokyoJapan
| | - Fumiyuki Takahashi
- Department of Respiratory MedicineJuntendo University Faculty of Medicine and Graduate School of MedicineTokyoJapan
| | - Masakazu Matsushita
- Department of Internal Medicine and RheumatologyJuntendo University Faculty of Medicine and Graduate School of MedicineTokyoJapan
| | - Yusuke Joki
- Department of Cardiovascular MedicineJuntendo University Faculty of Medicine and Graduate School of MedicineTokyoJapan
| | - Hakuoh Konishi
- Department of Cardiovascular MedicineJuntendo University Faculty of Medicine and Graduate School of MedicineTokyoJapan
| | - Satoshi Nunomura
- Division of Medical Biochemistry, Department of Biomolecular SciencesSaga Medical SchoolSagaJapan
| | - Kenji Izuhara
- Division of Medical Biochemistry, Department of Biomolecular SciencesSaga Medical SchoolSagaJapan
| | - Simon J. Conway
- Wells Center for Pediatric ResearchIndiana University School of MedicineIndianapolisIndianaUSA
| | - Kazuhisa Takahashi
- Department of Respiratory MedicineJuntendo University Faculty of Medicine and Graduate School of MedicineTokyoJapan
| |
Collapse
|
36
|
Chen J, Rodriguez M, Miao J, Liao J, Jain PP, Zhao M, Zhao T, Babicheva A, Wang Z, Parmisano S, Powers R, Matti M, Paquin C, Soroureddin Z, Shyy JYJ, Thistlethwaite PA, Makino A, Wang J, Yuan JXJ. Mechanosensitive channel Piezo1 is required for pulmonary artery smooth muscle cell proliferation. Am J Physiol Lung Cell Mol Physiol 2022; 322:L737-L760. [PMID: 35318857 PMCID: PMC9076422 DOI: 10.1152/ajplung.00447.2021] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 03/10/2022] [Accepted: 03/17/2022] [Indexed: 01/10/2023] Open
Abstract
Concentric pulmonary vascular wall thickening due partially to increased pulmonary artery (PA) smooth muscle cell (PASMC) proliferation contributes to elevating pulmonary vascular resistance (PVR) in patients with pulmonary hypertension (PH). Although pulmonary vasoconstriction may be an early contributor to increasing PVR, the transition of contractile PASMCs to proliferative PASMCs may play an important role in the development and progression of pulmonary vascular remodeling in PH. A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) is a trigger for PASMC contraction and proliferation. Here, we report that upregulation of Piezo1, a mechanosensitive cation channel, is involved in the contractile-to-proliferative phenotypic transition of PASMCs and potential development of pulmonary vascular remodeling. By comparing freshly isolated PA (contractile PASMCs) and primary cultured PASMCs (from the same rat) in a growth medium (proliferative PASMCs), we found that Piezo1, Notch2/3, and CaSR protein levels were significantly higher in proliferative PASMCs than in contractile PASMCs. Upregulated Piezo1 was associated with an increase in expression of PCNA, a marker for cell proliferation, whereas downregulation (with siRNA) or inhibition (with GsMTx4) of Piezo1 attenuated PASMC proliferation. Furthermore, Piezo1 in the remodeled PA from rats with experimental PH was upregulated compared with PA from control rats. These data indicate that PASMC contractile-to-proliferative phenotypic transition is associated with the transition or adaptation of membrane channels and receptors. Upregulated Piezo1 may play a critical role in PASMC phenotypic transition and PASMC proliferation. Upregulation of Piezo1 in proliferative PASMCs may likely be required to provide sufficient Ca2+ to assure nuclear/cell division and PASMC proliferation, contributing to the development and progression of pulmonary vascular remodeling in PH.
Collapse
Affiliation(s)
- Jiyuan Chen
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
- State Key Laboratory of Respiratory Disease and First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Marisela Rodriguez
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Jinrui Miao
- State Key Laboratory of Respiratory Disease and First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jing Liao
- State Key Laboratory of Respiratory Disease and First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Pritesh P Jain
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Manjia Zhao
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Tengteng Zhao
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Aleksandra Babicheva
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Ziyi Wang
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
- State Key Laboratory of Respiratory Disease and First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Sophia Parmisano
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Ryan Powers
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Moreen Matti
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Cole Paquin
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Zahra Soroureddin
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| | - John Y-J Shyy
- Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Patricia A Thistlethwaite
- Division of Cardiothoracic Surgery, Department of Surgery, University of California, San Diego, La Jolla, California
| | - Ayako Makino
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Jian Wang
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
- State Key Laboratory of Respiratory Disease and First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jason X-J Yuan
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| |
Collapse
|
37
|
Solinc J, Ribot J, Soubrier F, Pavoine C, Dierick F, Nadaud S. The Platelet-Derived Growth Factor Pathway in Pulmonary Arterial Hypertension: Still an Interesting Target? Life (Basel) 2022; 12:life12050658. [PMID: 35629326 PMCID: PMC9143262 DOI: 10.3390/life12050658] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 04/22/2022] [Accepted: 04/25/2022] [Indexed: 12/03/2022] Open
Abstract
The lack of curative options for pulmonary arterial hypertension drives important research to understand the mechanisms underlying this devastating disease. Among the main identified pathways, the platelet-derived growth factor (PDGF) pathway was established to control vascular remodeling and anti-PDGF receptor (PDGFR) drugs were shown to reverse the disease in experimental models. Four different isoforms of PDGF are produced by various cell types in the lung. PDGFs control vascular cells migration, proliferation and survival through binding to their receptors PDGFRα and β. They elicit multiple intracellular signaling pathways which have been particularly studied in pulmonary smooth muscle cells. Activation of the PDGF pathway has been demonstrated both in patients and in pulmonary hypertension (PH) experimental models. Tyrosine kinase inhibitors (TKI) are numerous but without real specificity and Imatinib, one of the most specific, resulted in beneficial effects. However, adverse events and treatment discontinuation discouraged to pursue this therapy. Novel therapeutic strategies are currently under experimental evaluation. For TKI, they include intratracheal drug administration, low dosage or nanoparticles delivery. Specific anti-PDGF and anti-PDGFR molecules can also be designed such as new TKI, soluble receptors, aptamers or oligonucleotides.
Collapse
Affiliation(s)
- Julien Solinc
- INSERM, Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, UMR_S1166, F-75013 Paris, France; (J.S.); (J.R.); (F.S.); (C.P.)
| | - Jonathan Ribot
- INSERM, Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, UMR_S1166, F-75013 Paris, France; (J.S.); (J.R.); (F.S.); (C.P.)
| | - Florent Soubrier
- INSERM, Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, UMR_S1166, F-75013 Paris, France; (J.S.); (J.R.); (F.S.); (C.P.)
| | - Catherine Pavoine
- INSERM, Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, UMR_S1166, F-75013 Paris, France; (J.S.); (J.R.); (F.S.); (C.P.)
| | - France Dierick
- Lady Davis Institute for Medical Research, McGill University, Montreal, QC H3T 1E2, Canada;
| | - Sophie Nadaud
- INSERM, Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, UMR_S1166, F-75013 Paris, France; (J.S.); (J.R.); (F.S.); (C.P.)
- Correspondence: ; Tel.: +33-14077-9681
| |
Collapse
|
38
|
Proteasome Inhibitors Decrease the Viability of Pulmonary Arterial Smooth Muscle Cells by Restoring Mitofusin-2 Expression under Hypoxic Conditions. Biomedicines 2022; 10:biomedicines10040873. [PMID: 35453623 PMCID: PMC9030547 DOI: 10.3390/biomedicines10040873] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/01/2022] [Accepted: 04/07/2022] [Indexed: 02/04/2023] Open
Abstract
Pulmonary hypertension (PH) is a severe progressive disease, and the uncontrolled proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the main causes. Mitofusin-2 (MFN2) profoundly inhibits cell growth and proliferation in a variety of tumor cell lines and rat vascular smooth muscle cells. Down-regulation of MFN2 is known to contribute to PH. Proteasome inhibitors have been shown to inhibit the proliferation of PASMCs; however, there is no study on the regulation of proteasome inhibitors through MFN-2 in the proliferation of PASMCs, a main pathophysiology of PH. In this study, PASMCs were exposed to hypoxic conditions and the expression of MFN2 and cleaved-PARP1 were detected by Western blotting. The effects of hypoxia and proteasome inhibitors on the cell viability of PASMC cells were detected by CCK8 assay. The results indicated that hypoxia increases the viability and reduces the expression of MFN2 in a PASMCs model. MFN2 overexpression inhibits the hypoxia-induced proliferation of PASMCs. In addition, proteasome inhibitors, bortezomib and marizomib, restored the decreased expression of MFN2 under hypoxic conditions, inhibited hypoxia-induced proliferation and induced the expression of cleaved-PARP1. These results suggest that bortezomib and marizomib have the potential to improve the hypoxia-induced proliferation of PASMCs by restoring MFN2 expression.
Collapse
|
39
|
Gomes MT, Bai Y, Potje SR, Zhang L, Lockett AD, Machado RF. Signal Transduction during Metabolic and Inflammatory Reprogramming in Pulmonary Vascular Remodeling. Int J Mol Sci 2022; 23:2410. [PMID: 35269553 PMCID: PMC8910500 DOI: 10.3390/ijms23052410] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 02/17/2022] [Indexed: 11/17/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by (mal)adaptive remodeling of the pulmonary vasculature, which is associated with inflammation, fibrosis, thrombosis, and neovascularization. Vascular remodeling in PAH is associated with cellular metabolic and inflammatory reprogramming that induce profound endothelial and smooth muscle cell phenotypic changes. Multiple signaling pathways and regulatory loops act on metabolic and inflammatory mediators which influence cellular behavior and trigger pulmonary vascular remodeling in vivo. This review discusses the role of bioenergetic and inflammatory impairments in PAH development.
Collapse
Affiliation(s)
- Marta T. Gomes
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; (Y.B.); (S.R.P.); (A.D.L.)
| | - Yang Bai
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; (Y.B.); (S.R.P.); (A.D.L.)
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Simone R. Potje
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; (Y.B.); (S.R.P.); (A.D.L.)
- Department of Biological Science, Minas Gerais State University (UEMG), Passos 37900-106, Brazil
| | - Lu Zhang
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China;
| | - Angelia D. Lockett
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; (Y.B.); (S.R.P.); (A.D.L.)
| | - Roberto F. Machado
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; (Y.B.); (S.R.P.); (A.D.L.)
| |
Collapse
|
40
|
Jain PP, Lai N, Xiong M, Chen J, Babicheva A, Zhao T, Parmisano S, Zhao M, Paquin C, Matti M, Powers R, Balistrieri A, Kim NH, Valdez-Jasso D, Thistlethwaite PA, Shyy JYJ, Wang J, Garcia JGN, Makino A, Yuan JXJ. TRPC6, a therapeutic target for pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2021; 321:L1161-L1182. [PMID: 34704831 PMCID: PMC8715021 DOI: 10.1152/ajplung.00159.2021] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 10/19/2021] [Accepted: 10/20/2021] [Indexed: 12/20/2022] Open
Abstract
Idiopathic pulmonary arterial hypertension (PAH) is a fatal and progressive disease. Sustained vasoconstriction due to pulmonary arterial smooth muscle cell (PASMC) contraction and concentric arterial remodeling due partially to PASMC proliferation are the major causes for increased pulmonary vascular resistance and increased pulmonary arterial pressure in patients with precapillary pulmonary hypertension (PH) including PAH and PH due to respiratory diseases or hypoxemia. We and others observed upregulation of TRPC6 channels in PASMCs from patients with PAH. A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) in PASMC triggers PASMC contraction and vasoconstriction, while Ca2+-dependent activation of PI3K/AKT/mTOR pathway is a pivotal signaling cascade for cell proliferation and gene expression. Despite evidence supporting a pathological role of TRPC6, no selective and orally bioavailable TRPC6 antagonist has yet been developed and tested for treatment of PAH or PH. In this study, we sought to investigate whether block of receptor-operated Ca2+ channels using a nonselective blocker of cation channels, 2-aminoethyl diphenylborinate (2-APB, administered intraperitoneally) and a selective blocker of TRPC6, BI-749327 (administered orally) can reverse established PH in mice. The results from the study show that intrapulmonary application of 2-APB (40 µM) or BI-749327 (3-10 µM) significantly and reversibly inhibited acute alveolar hypoxia-induced pulmonary vasoconstriction. Intraperitoneal injection of 2-APB (1 mg/kg per day) significantly attenuated the development of PH and partially reversed established PH in mice. Oral gavage of BI-749327 (30 mg/kg, every day, for 2 wk) reversed established PH by ∼50% via regression of pulmonary vascular remodeling. Furthermore, 2-APB and BI-749327 both significantly inhibited PDGF- and serum-mediated phosphorylation of AKT and mTOR in PASMC. In summary, the receptor-operated and mechanosensitive TRPC6 channel is a good target for developing novel treatment for PAH/PH. BI-749327, a selective TRPC6 blocker, is potentially a novel and effective drug for treating PAH and PH due to respiratory diseases or hypoxemia.
Collapse
MESH Headings
- Animals
- Boron Compounds/pharmacology
- Calcium Signaling
- Cells, Cultured
- Gene Expression Regulation/drug effects
- Humans
- Hypertension, Pulmonary/drug therapy
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/pathology
- Mice
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Phosphatidylinositol 3-Kinases/genetics
- Phosphatidylinositol 3-Kinases/metabolism
- Pulmonary Artery/drug effects
- Pulmonary Artery/metabolism
- Pulmonary Artery/pathology
- TOR Serine-Threonine Kinases/genetics
- TOR Serine-Threonine Kinases/metabolism
- TRPC6 Cation Channel/antagonists & inhibitors
- TRPC6 Cation Channel/genetics
- TRPC6 Cation Channel/metabolism
- Vasoconstriction
Collapse
Affiliation(s)
- Pritesh P Jain
- Section of Physiology, University of California, San Diego, La Jolla, California
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Ning Lai
- Section of Physiology, University of California, San Diego, La Jolla, California
- State Key Laboratory of Respiratory Medicine and First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mingmei Xiong
- Section of Physiology, University of California, San Diego, La Jolla, California
- State Key Laboratory of Respiratory Medicine and First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiyuan Chen
- Section of Physiology, University of California, San Diego, La Jolla, California
- State Key Laboratory of Respiratory Medicine and First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Aleksandra Babicheva
- Section of Physiology, University of California, San Diego, La Jolla, California
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Tengteng Zhao
- Section of Physiology, University of California, San Diego, La Jolla, California
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Sophia Parmisano
- Section of Physiology, University of California, San Diego, La Jolla, California
| | - Manjia Zhao
- Section of Physiology, University of California, San Diego, La Jolla, California
| | - Cole Paquin
- Section of Physiology, University of California, San Diego, La Jolla, California
| | - Moreen Matti
- Section of Physiology, University of California, San Diego, La Jolla, California
| | - Ryan Powers
- Section of Physiology, University of California, San Diego, La Jolla, California
| | - Angela Balistrieri
- Section of Physiology, University of California, San Diego, La Jolla, California
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Nick H Kim
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Daniela Valdez-Jasso
- Department of Bioengineering, University of California, San Diego, La Jolla, California
| | - Patricia A Thistlethwaite
- Division of Cardiothoracic Surgery, Department of Surgery, University of California, San Diego, La Jolla, California
| | - John Y-J Shyy
- Division of Cardiovascular Medicine, University of California, San Diego, La Jolla, California
| | - Jian Wang
- Section of Physiology, University of California, San Diego, La Jolla, California
- State Key Laboratory of Respiratory Medicine and First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Joe G N Garcia
- Department of Medicine, The University of Arizona, Tucson, Arizona
| | - Ayako Makino
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Jason X-J Yuan
- Section of Physiology, University of California, San Diego, La Jolla, California
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| |
Collapse
|
41
|
Wang Z, Chen J, Babicheva A, Jain PP, Rodriguez M, Ayon RJ, Ravellette KS, Wu L, Balistrieri F, Tang H, Wu X, Zhao T, Black SM, Desai AA, Garcia JGN, Sun X, Shyy JYJ, Valdez-Jasso D, Thistlethwaite PA, Makino A, Wang J, Yuan JXJ. Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension. Am J Physiol Cell Physiol 2021; 321:C1010-C1027. [PMID: 34669509 PMCID: PMC8714987 DOI: 10.1152/ajpcell.00147.2021] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 09/22/2021] [Accepted: 10/12/2021] [Indexed: 12/16/2022]
Abstract
Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca2+ and Na+ influx in multiple types of cells. Little is known about the functional role of Piezo1 in the lung vasculature and its potential pathogenic role in pulmonary arterial hypertension (PAH). Pulmonary arterial endothelial cells (PAECs) are constantly under mechanic stretch and shear stress that are sufficient to activate Piezo channels. Here, we report that Piezo1 is significantly upregulated in PAECs from patients with idiopathic PAH and animals with experimental pulmonary hypertension (PH) compared with normal controls. Membrane stretch by decreasing extracellular osmotic pressure or by cyclic stretch (18% CS) increases Ca2+-dependent phosphorylation (p) of AKT and ERK, and subsequently upregulates expression of Notch ligands, Jagged1/2 (Jag-1 and Jag-2), and Delta like-4 (DLL4) in PAECs. siRNA-mediated downregulation of Piezo1 significantly inhibited the stretch-mediated pAKT increase and Jag-1 upregulation, whereas downregulation of AKT by siRNA markedly attenuated the stretch-mediated Jag-1 upregulation in human PAECs. Furthermore, the mRNA and protein expression level of Piezo1 in the isolated pulmonary artery, which mainly contains pulmonary arterial smooth muscle cells (PASMCs), from animals with severe PH was also significantly higher than that from control animals. Intraperitoneal injection of a Piezo1 channel blocker, GsMTx4, ameliorated experimental PH in mice. Taken together, our study suggests that membrane stretch-mediated Ca2+ influx through Piezo1 is an important trigger for pAKT-mediated upregulation of Jag-1 in PAECs. Upregulation of the mechanosensitive channel Piezo1 and the resultant increase in the Notch ligands (Jag-1/2 and DLL4) in PAECs may play a critical pathogenic role in the development of pulmonary vascular remodeling in PAH and PH.
Collapse
Affiliation(s)
- Ziyi Wang
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
- Departments of Medicine and Physiology, The University of Arizona College of Medicine, Tucson, Arizona
- State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiyuan Chen
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
- State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Aleksandra Babicheva
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Pritesh P Jain
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Marisela Rodriguez
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
- Departments of Medicine and Physiology, The University of Arizona College of Medicine, Tucson, Arizona
| | - Ramon J Ayon
- Departments of Medicine and Physiology, The University of Arizona College of Medicine, Tucson, Arizona
| | - Keeley S Ravellette
- Departments of Medicine and Physiology, The University of Arizona College of Medicine, Tucson, Arizona
| | - Linda Wu
- Departments of Medicine and Physiology, The University of Arizona College of Medicine, Tucson, Arizona
| | - Francesca Balistrieri
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Haiyang Tang
- Departments of Medicine and Physiology, The University of Arizona College of Medicine, Tucson, Arizona
- State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaomin Wu
- Departments of Medicine and Physiology, The University of Arizona College of Medicine, Tucson, Arizona
| | - Tengteng Zhao
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Stephen M Black
- Departments of Medicine and Physiology, The University of Arizona College of Medicine, Tucson, Arizona
| | - Ankit A Desai
- Departments of Medicine and Physiology, The University of Arizona College of Medicine, Tucson, Arizona
- Department of Medicine, Indiana University, Indianapolis, Indiana
| | - Joe G N Garcia
- Departments of Medicine and Physiology, The University of Arizona College of Medicine, Tucson, Arizona
| | - Xin Sun
- Department of Pediatrics, University of California, San Diego, La Jolla, California
| | - John Y-J Shyy
- Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Daniela Valdez-Jasso
- Department of Bioengineering, University of California, San Diego, La Jolla, California
| | | | - Ayako Makino
- Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California
- Departments of Medicine and Physiology, The University of Arizona College of Medicine, Tucson, Arizona
| | - Jian Wang
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
- State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jason X-J Yuan
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
- Departments of Medicine and Physiology, The University of Arizona College of Medicine, Tucson, Arizona
| |
Collapse
|
42
|
Abstract
Pulmonary arterial hypertension is characterized by obliteration and obstruction of the pulmonary arterioles that in turn results in high right ventricular afterload and right heart failure. The pathobiology of pulmonary arterial hypertension is complex, with contributions from multiple pathophysiologic processes that are regulated by a variety of molecular mechanisms. This nature likely explains the limited efficacy of our current therapies, which only target a small portion of the pathobiological mechanisms that underlie advanced disease. Here we review the pathobiology of pulmonary arterial hypertension, focusing on the systemic, cellular, and molecular mechanisms that underlie the disease.
Collapse
Affiliation(s)
- Sudarshan Rajagopal
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Room 128A Hanes House, 330 Trent Drive, Durham, NC 27710, USA.
| | - Yen-Rei A Yu
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, 12605 E. 16th Avenue, Aurora, CO 80045, USA
| |
Collapse
|
43
|
Chakraborty R, Chatterjee P, Dave JM, Ostriker AC, Greif DM, Rzucidlo EM, Martin KA. Targeting smooth muscle cell phenotypic switching in vascular disease. JVS Vasc Sci 2021; 2:79-94. [PMID: 34617061 PMCID: PMC8489222 DOI: 10.1016/j.jvssci.2021.04.001] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 04/01/2021] [Indexed: 12/26/2022] Open
Abstract
Objective The phenotypic plasticity of vascular smooth muscle cells (VSMCs) is central to vessel growth and remodeling, but also contributes to cardiovascular pathologies. New technologies including fate mapping, single cell transcriptomics, and genetic and pharmacologic inhibitors have provided fundamental new insights into the biology of VSMC. The goal of this review is to summarize the mechanisms underlying VSMC phenotypic modulation and how these might be targeted for therapeutic benefit. Methods We summarize findings from extensive literature searches to highlight recent discoveries in the mechanisms underlying VSMC phenotypic switching with particular relevance to intimal hyperplasia. PubMed was searched for publications between January 2001 and December 2020. Search terms included VSMCs, restenosis, intimal hyperplasia, phenotypic switching or modulation, and drug-eluting stents. We sought to highlight druggable pathways as well as recent landmark studies in phenotypic modulation. Results Lineage tracing methods have determined that a small number of mature VSMCs dedifferentiate to give rise to oligoclonal lesions in intimal hyperplasia and atherosclerosis. In atherosclerosis and aneurysm, single cell transcriptomics reveal a striking diversity of phenotypes that can arise from these VSMCs. Mechanistic studies continue to identify new pathways that influence VSMC phenotypic plasticity. We review the mechanisms by which the current drug-eluting stent agents prevent restenosis and note remaining challenges in peripheral and diabetic revascularization for which new approaches would be beneficial. We summarize findings on new epigenetic (DNA methylation/TET methylcytosine dioxygenase 2, histone deacetylation, bromodomain proteins), transcriptional (Hippo/Yes-associated protein, peroxisome proliferator-activity receptor-gamma, Notch), and β3-integrin-mediated mechanisms that influence VSMC phenotypic modulation. Pharmacologic and genetic targeting of these pathways with agents including ascorbic acid, histone deacetylase or bromodomain inhibitors, thiazolidinediones, and integrin inhibitors suggests potential therapeutic value in the setting of intimal hyperplasia. Conclusions Understanding the molecular mechanisms that underlie the remarkable plasticity of VSMCs may lead to novel approaches to treat and prevent cardiovascular disease and restenosis.
Collapse
Affiliation(s)
- Raja Chakraborty
- Department of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Conn.,Department of Pharmacology, Yale University School of Medicine, New Haven, Conn
| | - Payel Chatterjee
- Department of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Conn.,Department of Pharmacology, Yale University School of Medicine, New Haven, Conn
| | - Jui M Dave
- Department of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Conn.,Department of Genetics, Yale University School of Medicine, New Haven, Conn
| | - Allison C Ostriker
- Department of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Conn.,Department of Pharmacology, Yale University School of Medicine, New Haven, Conn
| | - Daniel M Greif
- Department of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Conn.,Department of Genetics, Yale University School of Medicine, New Haven, Conn
| | - Eva M Rzucidlo
- Department Surgery, Section of Vascular Surgery, McLeod Regional Medical Center, Florence, SC
| | - Kathleen A Martin
- Department of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Conn.,Department of Pharmacology, Yale University School of Medicine, New Haven, Conn
| |
Collapse
|
44
|
Karoor V, Swindle D, Pak DI, Strassheim D, Fini MA, Dempsey E, Stenmark KR, Hassell K, Nuss R, Buehler PW, Irwin DC. Evidence supporting a role for circulating macrophages in the regression of vascular remodeling following sub-chronic exposure to hemoglobin plus hypoxia. Pulm Circ 2021; 11:20458940211056806. [PMID: 34777787 PMCID: PMC8573496 DOI: 10.1177/20458940211056806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/12/2021] [Indexed: 11/15/2022] Open
Abstract
Macrophages are a heterogeneous population with both pro- and anti-inflammatory functions play an essential role in maintaining tissue homeostasis, promoting inflammation under pathological conditions, and tissue repair after injury. In pulmonary hypertension, the M1 phenotype is more pro-inflammatory compared to the M2 phenotype, which is involved in tissue repair. The role of macrophages in the initiation and progression of pulmonary hypertension is well studied. However, their role in the regression of established pulmonary hypertension is not well known. Rats chronically exposed to hemoglobin (Hb) plus hypoxia (HX) share similarities to humans with pulmonary hypertension associated with hemolytic disease, including the presence of a unique macrophage phenotype surrounding distal vessels that are associated with vascular remodeling. These lung macrophages are characterized by high iron content, HO-1, ET-1, and IL-6, and are recruited from the circulation. Depletion of macrophages in this model prevents the development of pulmonary hypertension and vascular remodeling. In this study, we specifically investigate the regression of pulmonary hypertension over a four-week duration after rats were removed from Hb + HX exposure with and without gadolinium chloride administration. Withdrawal of Hb + HX reversed systolic pressures and right ventricular function after Hb + Hx exposure in four weeks. Our data show that depleting circulating monocytes/macrophages during reversal prevents complete recovery of right ventricular systolic pressure and vascular remodeling in this rat model of pulmonary hypertension at four weeks post exposure. The data presented offer a novel insight into the role of macrophages in the processes of pulmonary hypertension regression in a rodent model of Hb + Hx-driven disease.
Collapse
Affiliation(s)
- Vijaya Karoor
- Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Delaney Swindle
- Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - David I Pak
- Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Derek Strassheim
- Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Mehdi A Fini
- Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Edward Dempsey
- Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
- Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Kurt R Stenmark
- Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Kathryn Hassell
- Division of Hematology Colorado Sickle Cell Treatment and Research Center, School of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, CO, USA
| | - Rachelle Nuss
- Division of Hematology Colorado Sickle Cell Treatment and Research Center, School of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, CO, USA
| | - Paul W. Buehler
- Department of Pathology, University of Maryland, Baltimore, MD, USA
- The Center for Blood Oxygen Transport, Department of Pediatrics, School of Medicine, Baltimore, MD, USA
| | - David C. Irwin
- Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| |
Collapse
|
45
|
Role of Vascular Smooth Muscle Cell Phenotype Switching in Arteriogenesis. Int J Mol Sci 2021; 22:ijms221910585. [PMID: 34638923 PMCID: PMC8508942 DOI: 10.3390/ijms221910585] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 09/26/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open
Abstract
Arteriogenesis is one of the primary physiological means by which the circulatory collateral system restores blood flow after significant arterial occlusion in peripheral arterial disease patients. Vascular smooth muscle cells (VSMCs) are the predominant cell type in collateral arteries and respond to altered blood flow and inflammatory conditions after an arterial occlusion by switching their phenotype between quiescent contractile and proliferative synthetic states. Maintaining the contractile state of VSMC is required for collateral vascular function to regulate blood vessel tone and blood flow during arteriogenesis, whereas synthetic SMCs are crucial in the growth and remodeling of the collateral media layer to establish more stable conduit arteries. Timely VSMC phenotype switching requires a set of coordinated actions of molecular and cellular mediators to result in an expansive remodeling of collaterals that restores the blood flow effectively into downstream ischemic tissues. This review overviews the role of VSMC phenotypic switching in the physiological arteriogenesis process and how the VSMC phenotype is affected by the primary triggers of arteriogenesis such as blood flow hemodynamic forces and inflammation. Better understanding the role of VSMC phenotype switching during arteriogenesis can identify novel therapeutic strategies to enhance revascularization in peripheral arterial disease.
Collapse
|
46
|
Evidence for Multiple Origins of De Novo Formed Vascular Smooth Muscle Cells in Pulmonary Hypertension: Challenging the Dominant Model of Pre-Existing Smooth Muscle Expansion. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18168584. [PMID: 34444333 PMCID: PMC8391896 DOI: 10.3390/ijerph18168584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/10/2021] [Accepted: 08/12/2021] [Indexed: 11/17/2022]
Abstract
Vascular remodeling is a prominent feature of pulmonary hypertension. This process involves increased muscularization of already muscularized vessels as well as neo-muscularization of non-muscularized vessels. The cell-of-origin of the newly formed vascular smooth muscle cells has been a subject of intense debate in recent years. Identifying these cells may have important clinical implications since it opens the door for attempts to therapeutically target the progenitor cells and/or reverse the differentiation of their progeny. In this context, the dominant model is that these cells derive from pre-existing smooth muscle cells that are activated in response to injury. In this mini review, we present the evidence that is in favor of this model and, at the same time, highlight other studies indicating that there are alternative cellular sources of vascular smooth muscle cells in pulmonary vascular remodeling.
Collapse
|
47
|
Rodriguez M, Chen J, Jain PP, Babicheva A, Xiong M, Li J, Lai N, Zhao T, Hernandez M, Balistrieri A, Parmisano S, Simonson T, Breen E, Valdez-Jasso D, Thistlethwaite PA, Shyy JYJ, Wang J, Garcia JGN, Makino A, Yuan JXJ. Upregulation of Calcium Homeostasis Modulators in Contractile-To-Proliferative Phenotypical Transition of Pulmonary Arterial Smooth Muscle Cells. Front Physiol 2021; 12:714785. [PMID: 34408668 PMCID: PMC8364962 DOI: 10.3389/fphys.2021.714785] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/13/2021] [Indexed: 12/14/2022] Open
Abstract
Excessive pulmonary artery (PA) smooth muscle cell (PASMC) proliferation and migration are implicated in the development of pathogenic pulmonary vascular remodeling characterized by concentric arterial wall thickening and arteriole muscularization in patients with pulmonary arterial hypertension (PAH). Pulmonary artery smooth muscle cell contractile-to-proliferative phenotypical transition is a process that promotes pulmonary vascular remodeling. A rise in cytosolic Ca2+ concentration [(Ca2+) cyt ] in PASMCs is a trigger for pulmonary vasoconstriction and a stimulus for pulmonary vascular remodeling. Here, we report that the calcium homeostasis modulator (CALHM), a Ca2+ (and ATP) channel that is allosterically regulated by voltage and extracellular Ca2+, is upregulated during the PASMC contractile-to-proliferative phenotypical transition. Protein expression of CALHM1/2 in primary cultured PASMCs in media containing serum and growth factors (proliferative PASMC) was significantly greater than in freshly isolated PA (contractile PASMC) from the same rat. Upregulated CALHM1/2 in proliferative PASMCs were associated with an increased ratio of pAKT/AKT and pmTOR/mTOR and an increased expression of the cell proliferation marker PCNA, whereas serum starvation and rapamycin significantly downregulated CALHM1/2. Furthermore, CALHM1/2 were upregulated in freshly isolated PA from rats with monocrotaline (MCT)-induced PH and in primary cultured PASMC from patients with PAH in comparison to normal controls. Intraperitoneal injection of CGP 37157 (0.6 mg/kg, q8H), a non-selective blocker of CALHM channels, partially reversed established experimental PH. These data suggest that CALHM upregulation is involved in PASMC contractile-to-proliferative phenotypical transition. Ca2+ influx through upregulated CALHM1/2 may play an important role in the transition of sustained vasoconstriction to excessive vascular remodeling in PAH or precapillary PH. Calcium homeostasis modulator could potentially be a target to develop novel therapies for PAH.
Collapse
Affiliation(s)
- Marisela Rodriguez
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
- Department of Pediatrics, Tucson, AZ, United States
| | - Jiyuan Chen
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
- State Key Laboratory of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Pritesh P. Jain
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
| | - Aleksandra Babicheva
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
| | - Mingmei Xiong
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
- State Key Laboratory of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jifeng Li
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
- Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Ning Lai
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
- State Key Laboratory of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Tengteng Zhao
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
| | - Moises Hernandez
- Division of Cardiothoracic Surgery, Department of Surgery, La Jolla, CA, United States
| | - Angela Balistrieri
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
| | - Sophia Parmisano
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
| | - Tatum Simonson
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
| | - Ellen Breen
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
| | - Daniela Valdez-Jasso
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, United States
| | | | - John Y. -J. Shyy
- Division of Cardiovascular Medicine, Department of Medicine, La Jolla, CA, United States
| | - Jian Wang
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
- State Key Laboratory of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Joe G. N. Garcia
- Department of Medicine, The University of Arizona, Tucson, AZ, United States
| | - Ayako Makino
- Division of Endocrinology and Metabolism, La Jolla, CA, United States
| | - Jason X. -J. Yuan
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, La Jolla, CA, United States
| |
Collapse
|