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1
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Lee C, Kim MJ, Kumar A, Lee HW, Yang Y, Kim Y. Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives. Signal Transduct Target Ther 2025; 10:170. [PMID: 40383803 DOI: 10.1038/s41392-025-02249-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/09/2025] [Accepted: 04/21/2025] [Indexed: 05/20/2025] Open
Abstract
Vascular endothelial growth factor (VEGF) signaling is a critical regulator of vasculogenesis, angiogenesis, and lymphangiogenesis, processes that are vital for the development of vascular and lymphatic systems, tissue repair, and the maintenance of homeostasis. VEGF ligands and their receptors orchestrate endothelial cell proliferation, migration, and survival, playing a pivotal role in dynamic vascular remodeling. Dysregulated VEGF signaling drives diverse pathological conditions, including tumor angiogenesis, cardiovascular diseases, and ocular disorders. Excessive VEGF activity promotes tumor growth, invasion, and metastasis, while insufficient signaling contributes to impaired wound healing and ischemic diseases. VEGF-targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have revolutionized the treatment of diseases involving pathological angiogenesis, offering significant clinical benefits in oncology and ophthalmology. These therapies inhibit angiogenesis and slow disease progression, but they often face challenges such as therapeutic resistance, suboptimal efficacy, and adverse effects. To further explore these issues, this review provides a comprehensive overview of VEGF ligands and receptors, elucidating their molecular mechanisms and regulatory networks. It evaluates the latest progress in VEGF-targeted therapies and examines strategies to address current challenges, such as resistance mechanisms. Moreover, the discussion includes emerging therapeutic strategies such as innovative drug delivery systems and combination therapies, highlighting the continuous efforts to improve the effectiveness and safety of VEGF-targeted treatments. This review highlights the translational potential of recent discoveries in VEGF biology for improving patient outcomes.
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Affiliation(s)
- Chunsik Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea.
| | - Myung-Jin Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea
| | - Anil Kumar
- Center for Research and Innovations, Adichunchanagiri University, Mandya, Karnataka, India
| | - Han-Woong Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yonghwan Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea.
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2
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Shi Z, Kuai M, Li B, Akowuah CF, Wang Z, Pan Y, Tang M, Yang X, Lü P. The role of VEGF in Cancer angiogenesis and tumorigenesis: Insights for anti-VEGF therapy. Cytokine 2025; 189:156908. [PMID: 40049050 DOI: 10.1016/j.cyto.2025.156908] [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: 01/07/2025] [Revised: 02/16/2025] [Accepted: 02/28/2025] [Indexed: 03/18/2025]
Abstract
Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis, playing a pivotal role in both physiological and pathological processes. It promotes the formation of new blood vessels and activates downstream signaling pathways that regulate endothelial cell function. This review highlights recent advancements in the understanding of VEGF's molecular structure and its isoforms, as well as their implications in disease progression. It also explores the mechanisms of VEGF inhibitors. While VEGF inhibitors show promise in the treatment of cancer and other diseases, their clinical use faces significant challenges, including drug resistance, side effects, and complex interactions with other signaling pathways. To address these challenges, future research should focus on: (i) enhancing the understanding of VEGF subtypes and their distinct roles in various diseases, supporting the development of personalized treatment strategies; (ii) developing combination therapies that integrate VEGF inhibitors with other targeted treatments to overcome resistance and improve efficacy; (iii) optimizing drug delivery systems to reduce off-target effects and enhance therapeutic outcomes. These approaches aim to improve the effectiveness and safety of VEGF-targeted therapies, offering new possibilities for the treatment of VEGF-related diseases.
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Affiliation(s)
- Zijun Shi
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Mengmeng Kuai
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Baohua Li
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | | | - Zhenyu Wang
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Ye Pan
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Min Tang
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Xiaoyue Yang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai 200030, China.
| | - Peng Lü
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; Affiliated Hospital of Jiangsu University, Zhenjiang 212013, China.
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3
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Aksan B, Mauceri D. Beyond vessels: unraveling the impact of VEGFs on neuronal functions and structure. J Biomed Sci 2025; 32:33. [PMID: 40050849 PMCID: PMC11884128 DOI: 10.1186/s12929-025-01128-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 02/21/2025] [Indexed: 03/10/2025] Open
Abstract
Neurons rely on the bloodstream for essential nutrients and oxygen, which is facilitated by an intricate coupling of the neuronal and vascular systems. Central to this neurovascular interaction is the vascular endothelial growth factor (VEGF) family, a group of secreted growth factors traditionally known for their roles in promoting endothelial cell proliferation, migration, and survival in the cardiovascular and lymphatic systems. However, emerging evidence shows that VEGFs also play indispensable roles in the nervous system, extending beyond their canonical angiogenic and lymphangiogenic functions. Over the past two decades, VEGFs have been found to exert direct effects on neurons, influencing key aspects of neuronal function independently of their actions on vascular cells. In particular, it has become increasingly evident that VEGFs also play crucial functions in the development, regulation, and maintenance of neuronal morphology. Understanding the roles of VEGFs in neuronal development is of high scientific and clinical interest because of the significance of precise neuronal morphology for neural connectivity and network function, as well as the association of morphological abnormalities with neurological and neurodegenerative disorders. This review begins with an overview of the VEGF family members, their structural characteristics, receptors, and established roles in vasculature. However, it then highlights and focuses on the exciting variety of neuronal functions of VEGFs, especially their crucial role in the development, regulation, and maintenance of neuronal morphology.
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Affiliation(s)
- Bahar Aksan
- Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), Heidelberg University, INF 366, 69120, Heidelberg, Germany
| | - Daniela Mauceri
- Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), Heidelberg University, INF 366, 69120, Heidelberg, Germany.
- Institute of Anatomy and Cell Biology, Dept. Molecular and Cellular Neuroscience, University of Marburg, Robert-Koch-Str. 8, 35032, Marburg, Germany.
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4
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Yang J, Li C, Wang Z, Jiang K. Multi-omics analysis of the biological function of the VEGF family in colon adenocarcinoma. Funct Integr Genomics 2024; 24:210. [PMID: 39527375 PMCID: PMC11554882 DOI: 10.1007/s10142-024-01493-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/10/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
The vascular endothelial growth factor (VEGF) family plays a crucial role in cancer progression, but the prognostic significance and biological functions of VEGF family members in colon adenocarcinoma (COAD) remain unclear. Using data from The Cancer Genome Atlas, Gene Expression Omnibus, Gene Set Cancer Analysis, cBioPortal, GeneMANIA, String, MethSurv and starBase database, we identified vascular endothelial growth factor B (VEGFB) as a key gene associated with COAD prognosis, with its abnormal expression linked to methylation dysregulation. In vitro experiments confirmed VEGFB expression was significantly higher in colon cancer tissues compared to normal tissues, as shown by Real-time quantitative PCR and immunohistochemistry. Cell Counting Kit-8 and colony formation assay showed that decreased VEGFB expression in SW480 cells resulted in decreased cell viability and proliferation ability. Scratch assay showed that VEGFB downregulation impaired SW480 cell migration. In addition, our research suggests that VEGFB not only promotes angiogenesis but is also involved in the tumor microenvironment and immune regulation. The SHNG17-miR-375-VEGFB regulatory axis provides a potential therapeutic target for COAD, highlighting VEGFB's role in immune activation during anti-angiogenic therapy and potential reversal of drug resistance.
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Affiliation(s)
- Jianqiao Yang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Chen Li
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Zhu Wang
- Department of Gastroenterological Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Kewei Jiang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China.
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5
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Wazan LE, Widhibrata A, Liu GS. Soluble FLT-1 in angiogenesis: pathophysiological roles and therapeutic implications. Angiogenesis 2024; 27:641-661. [PMID: 39207600 DOI: 10.1007/s10456-024-09942-8] [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: 06/29/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
Fine-tuning angiogenesis, the development of new blood vessels, is essential for maintaining a healthy circulatory and lymphatic system. The small glycoprotein vascular endothelial growth factors (VEGF) are the key mediators in this process, binding to their corresponding membrane-bound VEGF receptors (VEGFRs) to activate angiogenesis signaling pathways. These pathways are crucial throughout human life as they are involved in lymphatic and vascular endothelial cell permeability, migration, proliferation, and survival. Neovascularization, the formation of abnormal blood vessels, occurs when there is a dysregulation of angiogenesis and can result in debilitating disease. Hence, VEGFRs have been widely studied to understand their role in disease-causing angiogenesis. VEGFR1, also known as Fms-like tyrosine kinase-1 (FLT-1), is also found in a soluble form, soluble FLT-1 or sFLT-1, which is known to act as a VEGF neutralizer. It is incorporated into anti-VEGF therapy, designed to treat diseases caused by neovascularization. Here we review the journey of sFLT-1 discovery and delve into the alternative splicing mechanism that creates the soluble receptor, its prevalence in disease states, and its use in current and future potential therapies.
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Affiliation(s)
- Layal Ei Wazan
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Level 7, 32 Gisborne Street, East Melbourne, VIC, 3002, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia
| | - Ariel Widhibrata
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Level 7, 32 Gisborne Street, East Melbourne, VIC, 3002, Australia
| | - Guei-Sheung Liu
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Level 7, 32 Gisborne Street, East Melbourne, VIC, 3002, Australia.
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia.
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
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Nilsson I, Su EJ, Fredriksson L, Sahlgren BH, Bagoly Z, Moessinger C, Stefanitsch C, Ning FC, Zeitelhofer M, Muhl L, Lawrence ALE, Scotney PD, Lu L, Samén E, Ho H, Keep RF, Medcalf RL, Lawrence DA, Eriksson U. Thrombolysis exacerbates cerebrovascular injury after ischemic stroke via a VEGF-B dependent effect on adipose lipolysis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.11.617532. [PMID: 39416206 PMCID: PMC11483068 DOI: 10.1101/2024.10.11.617532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Cerebrovascular injuries leading to edema and hemorrhage after ischemic stroke are common. The mechanisms underlying these events and how they are connected to known risk factors for poor outcome, like obesity and diabetes, is relatively unknown. Herein we demonstrate that increased adipose tissue lipolysis is a dominating risk factor for the development of a compromised cerebrovasculature in ischemic stroke. Reducing adipose lipolysis by VEGF-B antagonism improved vascular integrity by reducing ectopic cerebrovascular lipid deposition. Thrombolytic therapy in ischemic stroke using tissue plasminogen activator (tPA) leads to increased risk of hemorrhagic complications, substantially limiting the use of thrombolytic therapy. We provide evidence that thrombolysis with tPA promotes adipose tissue lipolysis, leading to a rise in plasma fatty acids and lipid accumulation in the ischemic cerebrovasculature after stroke. VEGF-B blockade improved the efficacy and safety of thrombolysis suggesting the potential use of anti-VEGF-B therapy to extend the therapeutic window for stroke management.
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Affiliation(s)
- Ingrid Nilsson
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
- These authors contributed equally
- Lead contact: (I.N.)
| | - Enming J. Su
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
- These authors contributed equally
| | - Linda Fredriksson
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Benjamin Heller Sahlgren
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Zsuzsa Bagoly
- MTA-DE Lendület “Momentum” Hemostasis and Stroke Research Group, Department of Laboratory Medicine, Division of Clinical Laboratory Sciences, Faculty of Medicine, University of Debrecen, Hungary
| | - Christine Moessinger
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Christina Stefanitsch
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Frank Chenfei Ning
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Manuel Zeitelhofer
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Lars Muhl
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Anna-Lisa E. Lawrence
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | | | - Li Lu
- Karolinska Experimental Research and Imaging Centre, Karolinska University Hospital, Stockholm, Sweden
| | - Erik Samén
- Department of Nuclear Medicine and Medical Physics, Karolinska University Hospital, Stockholm, Sweden
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Heidi Ho
- Australian Centre for Blood Diseases, Monash University, Melbourne 3004, Victoria, Australia
| | - Richard F. Keep
- Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA
| | - Robert L. Medcalf
- Australian Centre for Blood Diseases, Monash University, Melbourne 3004, Victoria, Australia
| | - Daniel A. Lawrence
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ulf Eriksson
- Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden
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7
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Pelayo R, Gutiérrez-Gil B, Marina H, Fonseca PAS, Alonso-García M, Arranz JJ, Suárez-Vega A. Unraveling Dynamic Transcriptomic Changes in Sheep's Lactating Mammary Gland Following Escherichia coli Lipopolysaccharide Exposure. J Dairy Sci 2024:S0022-0302(24)01149-4. [PMID: 39343208 DOI: 10.3168/jds.2024-25009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 08/16/2024] [Indexed: 10/01/2024]
Abstract
Mammary gland infections constitute a significant challenge in dairy sheep, impacting productivity and welfare. Temporal RNA-Seq provide a valuable approach to evaluate the evolution of the host defensive molecular mechanisms triggered by mastitis caused by external agents or events. This study aimed to characterize the transcriptomic response of sheep mammary glands to an intramammary inflammation induced with an Escherichia coli lipopolysaccharide (LPS) inoculation based on RNA-Seq samples generated from milk somatic cells collected at 3 time points: pre-inoculation (0 h), and 6 h and 24 h post-LPS inoculation. The differential expression analyses between the analyzed time points were performed using 2 statistical approaches: one parametric (DESeq2) and one non-parametric (Wilcoxon rank sum test). The differentially expressed genes (DEGs) commonly identified by both approaches encompass 5,872 for the 0 h versus 6 h comparison, 4,063 for the 0 h versus 24 h comparison, and 1,034 for the 6 h versus 24 h comparison. At both 6 h and 24 h, transcriptomic data highlighted a significant decrease in the expression of genes linked to metabolic processes crucial for milk protein and lipid synthesis within the mammary gland. Concurrently, increased expression of genes related to the neutrophil attraction was observed for 6 and 24 h, with differences in gene expression between DEGs with the highest expression at 6 h, related to T cell activation, type I interferon-mediated signaling pathway, and 24 h, related to cell-cell neutrophil adhesion extravasation or epithelial cell proliferation. In summary, this study reveals how the sheep mammary gland transcriptome responds dynamically to an LPS inoculation, providing a comprehensive understanding of how gene expression patterns evolve over time and shedding light on the molecular mechanisms driving the initial defensive response of the mammary gland against potential inflammatory challenges.
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Affiliation(s)
- R Pelayo
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain
| | - B Gutiérrez-Gil
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain
| | - H Marina
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain
| | - P A S Fonseca
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain
| | - M Alonso-García
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain
| | - J J Arranz
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain
| | - A Suárez-Vega
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain..
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Xu Y, Peng Y, Wu X, Ni F, Sun D, Zhang P, Yang Y, Yan M, Mi J, Tian G. VEGF-B prevents chronic hyperglycemia-induced retinal vascular leakage by regulating the CDC42-ZO1/VE-cadherin pathway. FASEB J 2024; 38:e70019. [PMID: 39215561 DOI: 10.1096/fj.202300987rr] [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: 05/16/2023] [Revised: 08/05/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
Non-proliferative diabetic retinopathy (NPDR) is the early stage of diabetic retinopathy (DR) and is a chronic oxidative stress-related ocular disease. Few treatments are approved for early DR. This study aimed to investigate the pathogenic mechanisms underlying the retinal micro-vasculopathy induced by diabetes and to explore an early potential for treating early DR in a mouse model. The mouse model of type 1 diabetes was established by intraperitoneal injection of streptozotocin (STZ, 180 mg/kg), which was used as the early DR model. The body weight and blood glucose mice were measured regularly; The retinal vascular leakage in the early DR mice was determined by whole-mount staining; Label-free quantitative proteomic analysis and bioinformatics were used to explore the target proteins and signaling pathways associated with the retinal tissues of early DR mice; To detect the effects of target protein on endothelial cell proliferation, migration, and tube formation, knockdown and overexpression of VEGF-B were performed in human retinal vascular endothelial cells (HRECs); Western blotting was used to detect the expression of target proteins in vitro and in vivo; Meanwhile, the therapeutic effect of VEGF-B on vascular leakage has also been evaluated in vitro and in vivo. The protein expressions of vascular endothelial growth factor (VEGF)-B and the Rho GTPases family member CDC42 were reduced in the retinal tissues of early DR. VEGF-B upregulated the expression of CDC42/ZO1/VE-cadherin and prevented hyperglycemia-induced vascular leakage in HRECs. Standard intravitreal VEGF-B injections improved the retinal vascular leakage and neurovascular response in early DR mice. Our findings demonstrated, for the first time, that in diabetes, the retinal vessels are damaged due to decreased VEGF-B expression through downregulation of CDC42/ZO1/VE-cadherin expression. Therefore, VEGF-B could be used as a novel therapy for early DR.
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Affiliation(s)
- Yuxue Xu
- School of Pharmacy, Binzhou Medical University, Yantai, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, China
| | - Yue Peng
- School of Pharmacy, Binzhou Medical University, Yantai, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, China
| | - Xiaojun Wu
- School of Pharmacy, Binzhou Medical University, Yantai, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, China
| | - Feixue Ni
- School of Pharmacy, Binzhou Medical University, Yantai, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, China
| | - Daxi Sun
- School of Pharmacy, Binzhou Medical University, Yantai, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, China
| | - Pengfei Zhang
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, China
- School of Clinical Medicine, Binzhou Medical University, Yantai, China
| | - Yang Yang
- School of Pharmacy, Binzhou Medical University, Yantai, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, China
| | - Miao Yan
- School of Pharmacy, Binzhou Medical University, Yantai, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, China
| | - Jia Mi
- School of Pharmacy, Binzhou Medical University, Yantai, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, China
| | - Geng Tian
- School of Pharmacy, Binzhou Medical University, Yantai, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, China
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Guo Z, Jing X, Sun X, Sun S, Yang Y, Cao Y. Tumor angiogenesis and anti-angiogenic therapy. Chin Med J (Engl) 2024; 137:2043-2051. [PMID: 39051171 PMCID: PMC11374217 DOI: 10.1097/cm9.0000000000003231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Indexed: 07/27/2024] Open
Abstract
ABSTRACT Anti-angiogenic drugs (AADs), which mainly target the vascular endothelial growth factor-A signaling pathway, have become a therapeutic option for cancer patients for two decades. During this period, tremendous clinical experience of anti-angiogenic therapy has been acquired, new AADs have been developed, and the clinical indications for AAD treatment of various cancers have been expanded using monotherapy and combination therapy. However, improvements in the therapeutic outcomes of clinically available AADs and the development of more effective next-generation AADs are still urgently required. This review aims to provide historical and perspective views on tumor angiogenesis to allow readers to gain mechanistic insights and learn new therapeutic development. We revisit the history of concept initiation and AAD discovery, and summarize the up-to-date clinical translation of anti-angiogenic cancer therapy in this field.
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Affiliation(s)
- Ziheng Guo
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xu Jing
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm 17177, Sweden
| | - Xiaoting Sun
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm 17177, Sweden
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vison and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Shishuo Sun
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm 17177, Sweden
- Cancer Institute, the First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu 221000, China
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm 17177, Sweden
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10
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Zhou R, Xue Y, Zhu Z, Xu P, Shen L, Wang Z, Xiang Y, Cao Y, Yu X, Shang W. VEGF-B is involved in diabetic peripheral neuropathy in patients with type 2 diabetes. Growth Factors 2024; 42:101-110. [PMID: 39001597 DOI: 10.1080/08977194.2024.2377553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 07/03/2024] [Indexed: 11/12/2024]
Abstract
Aims: This study aims to explore the potential role of vascular endothelial growth factor-B (VEGF-B) in the pathogenesis of diabetic peripheral neuropathy (DPN). The expression of VEGFRs were reanalysed by using gene arrays of peripheral nerve samples from mouse models of DPN retrieved from the GEO database. 213 T2D patients as well as 31 healthy individuals were recruited. The serum VEGF-B was detected and its relationship with DPN was analysed. The elevated VEGFR1 was the only change of VEGFR gene expression in the peripheral nerve from mouse models of DPN. The level of serum VEGF-B in T2D patients with DPN was higher than that in T2D patients without DPN and healthy people. Analysis of correlation and binary logistic regression confirmed that the increased serum VEGF-B level was an independent risk factor of DPN in T2D patients. VEGF-B-VEGFR1 signaling pathway may be involved in the development of DPN.
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Affiliation(s)
- Ruonan Zhou
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yingying Xue
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ziwei Zhu
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Pingyuan Xu
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lixuan Shen
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ziwei Wang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yingying Xiang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yue Cao
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xizhong Yu
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenbin Shang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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11
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Sultan I, Ramste M, Peletier P, Hemanthakumar KA, Ramanujam D, Tirronen A, von Wright Y, Antila S, Saharinen P, Eklund L, Mervaala E, Ylä-Herttuala S, Engelhardt S, Kivelä R, Alitalo K. Contribution of VEGF-B-Induced Endocardial Endothelial Cell Lineage in Physiological Versus Pathological Cardiac Hypertrophy. Circ Res 2024; 134:1465-1482. [PMID: 38655691 PMCID: PMC11542978 DOI: 10.1161/circresaha.123.324136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 03/19/2024] [Accepted: 04/08/2024] [Indexed: 04/26/2024]
Abstract
BACKGROUND Preclinical studies have shown the therapeutic potential of VEGF-B (vascular endothelial growth factor B) in revascularization of the ischemic myocardium, but the associated cardiac hypertrophy and adverse side effects remain a concern. To understand the importance of endothelial proliferation and migration for the beneficial versus adverse effects of VEGF-B in the heart, we explored the cardiac effects of autocrine versus paracrine VEGF-B expression in transgenic and gene-transduced mice. METHODS We used single-cell RNA sequencing to compare cardiac endothelial gene expression in VEGF-B transgenic mouse models. Lineage tracing was used to identify the origin of a VEGF-B-induced novel endothelial cell population and adeno-associated virus-mediated gene delivery to compare the effects of VEGF-B isoforms. Cardiac function was investigated using echocardiography, magnetic resonance imaging, and micro-computed tomography. RESULTS Unlike in physiological cardiac hypertrophy driven by a cardiomyocyte-specific VEGF-B transgene (myosin heavy chain alpha-VEGF-B), autocrine VEGF-B expression in cardiac endothelium (aP2 [adipocyte protein 2]-VEGF-B) was associated with septal defects and failure to increase perfused subendocardial capillaries postnatally. Paracrine VEGF-B led to robust proliferation and myocardial migration of a novel cardiac endothelial cell lineage (VEGF-B-induced endothelial cells) of endocardial origin, whereas autocrine VEGF-B increased proliferation of VEGF-B-induced endothelial cells but failed to promote their migration and efficient contribution to myocardial capillaries. The surviving aP2-VEGF-B offspring showed an altered ratio of secreted VEGF-B isoforms and developed massive pathological cardiac hypertrophy with a distinct cardiac vessel pattern. In the normal heart, we found a small VEGF-B-induced endothelial cell population that was only minimally expanded during myocardial infarction but not during physiological cardiac hypertrophy associated with mouse pregnancy. CONCLUSIONS Paracrine and autocrine secretions of VEGF-B induce expansion of a specific endocardium-derived endothelial cell population with distinct angiogenic markers. However, autocrine VEGF-B signaling fails to promote VEGF-B-induced endothelial cell migration and contribution to myocardial capillaries, predisposing to septal defects and inducing a mismatch between angiogenesis and myocardial growth, which results in pathological cardiac hypertrophy.
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Affiliation(s)
- Ibrahim Sultan
- Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
- Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
| | - Markus Ramste
- Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
- Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
| | - Pim Peletier
- Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
- Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
| | - Karthik Amudhala Hemanthakumar
- Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
- Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
| | - Deepak Ramanujam
- Institute of Pharmacology and Toxicology, Technical University of Munich, DZHK partner site Munich Heart Alliance, Germany (D.R., S.E.)
- RNATICS GmbH, Planegg, Germany (D.R.)
| | - Annakaisa Tirronen
- A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (A.T., S.Y.-H.)
| | - Ylva von Wright
- Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
- Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
| | - Salli Antila
- Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
- Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
| | - Pipsa Saharinen
- Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
- Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
| | - Lauri Eklund
- Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Finland (L.E.)
| | - Eero Mervaala
- Department of Pharmacology (E.M.), Faculty of Medicine, University of Helsinki, Finland
| | - Seppo Ylä-Herttuala
- A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (A.T., S.Y.-H.)
| | - Stefan Engelhardt
- Institute of Pharmacology and Toxicology, Technical University of Munich, DZHK partner site Munich Heart Alliance, Germany (D.R., S.E.)
| | - Riikka Kivelä
- Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
- Stem Cells and Metabolism Research Program (R.K.), Faculty of Medicine, University of Helsinki, Finland
- Faculty of Sport and Health Sciences, University of Jyväskylä, Finland (R.K.)
| | - Kari Alitalo
- Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
- Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland
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12
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Zhang Z, Chen W, Sun M, Aalders T, Verhaegh GW, Kouwer PHJ. TempEasy 3D Hydrogel Coculture System Provides Mechanistic Insights into Prostate Cancer Bone Metastasis. ACS APPLIED MATERIALS & INTERFACES 2024; 16:25773-25787. [PMID: 38739686 PMCID: PMC11129143 DOI: 10.1021/acsami.4c03453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/01/2024] [Accepted: 05/02/2024] [Indexed: 05/16/2024]
Abstract
Patients diagnosed with advanced prostate cancer (PCa) often experience incurable bone metastases; however, a lack of relevant experimental models has hampered the study of disease mechanisms and the development of therapeutic strategies. In this study, we employed the recently established Temperature-based Easy-separable (TempEasy) 3D cell coculture system to investigate PCa bone metastasis. Through coculturing PCa and bone cells for 7 days, our results showed a reduction in PCa cell proliferation, an increase in neovascularization, and an enhanced metastasis potential when cocultured with bone cells. Additionally, we observed increased cell proliferation, higher stemness, and decreased bone matrix protein expression in bone cells when cocultured with PCa cells. Furthermore, we demonstrated that the stiffness of the extracellular matrix had a negligible impact on molecular responses in both primary (PCa cells) and distant malignant (bone cells) sites. The TempEasy 3D hydrogel coculture system is an easy-to-use and versatile coculture system that provides valuable insights into the mechanisms of cell-cell communication and interaction in cancer metastasis.
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Affiliation(s)
- Zhaobao Zhang
- Institute
for Molecules and Materials, Radboud University, Heyendaalseweg 135, Nijmegen 6525 AJ, The Netherlands
| | - Wen Chen
- Institute
for Molecules and Materials, Radboud University, Heyendaalseweg 135, Nijmegen 6525 AJ, The Netherlands
| | - Mingchen Sun
- Institute
for Molecules and Materials, Radboud University, Heyendaalseweg 135, Nijmegen 6525 AJ, The Netherlands
| | - Tilly Aalders
- Department
of Urology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Geert Grooteplein Zuid 28, Nijmegen 6525 GA, The Netherlands
| | - Gerald W. Verhaegh
- Department
of Urology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Geert Grooteplein Zuid 28, Nijmegen 6525 GA, The Netherlands
| | - Paul H. J. Kouwer
- Institute
for Molecules and Materials, Radboud University, Heyendaalseweg 135, Nijmegen 6525 AJ, The Netherlands
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13
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Malekan M, Haass NK, Rokni GR, Gholizadeh N, Ebrahimzadeh MA, Kazeminejad A. VEGF/VEGFR axis and its signaling in melanoma: Current knowledge toward therapeutic targeting agents and future perspectives. Life Sci 2024; 345:122563. [PMID: 38508233 DOI: 10.1016/j.lfs.2024.122563] [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: 01/20/2024] [Revised: 03/10/2024] [Accepted: 03/13/2024] [Indexed: 03/22/2024]
Abstract
Melanoma is responsible for most skin cancer-associated deaths globally. The progression of melanoma is influenced by a number of pathogenic processes. Understanding the VEGF/VEGFR axis, which includes VEGF-A, PlGF, VEGF-B, VEGF-C, and VEGF-D and their receptors, VEGFR-1, VEGFR-2, and VEGFR-3, is of great importance in melanoma due to its crucial role in angiogenesis. This axis generates multifactorial and complex cellular signaling, engaging the MAPK/ERK, PI3K/AKT, PKC, PLC-γ, and FAK signaling pathways. Melanoma cell growth and proliferation, migration and metastasis, survival, and acquired resistance to therapy are influenced by this axis. The VEGF/VEGFR axis was extensively examined for their potential as diagnostic/prognostic biomarkers in melanoma patients and results showed that VEGF overexpression can be associated with unfavorable prognosis, higher level of tumor invasion and poor response to therapy. MicroRNAs linking to the VEGF/VEGFR axis were identified and, in this review, divided into two categories according to their functions, some of them promote melanoma angiogenesis (promotive group) and some restrict melanoma angiogenesis (protective group). In addition, the approach of treating melanoma by targeting the VEGF/VEGFR axis has garnered significant interest among researchers. These agents can be divided into two main groups: anti-VEGF and VEGFR inhibitors. These therapeutic options may be a prominent step along with the modern targeting and immune therapies for better coverage of pathological processes leading to melanoma progression and therapy resistance.
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Affiliation(s)
- Mohammad Malekan
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | | | - Ghasem Rahmatpour Rokni
- Department of Dermatology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Nasim Gholizadeh
- Department of Dermatology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Ali Ebrahimzadeh
- Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Armaghan Kazeminejad
- Department of Dermatology, Antimicrobial Resistance Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences,Sari, Iran
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14
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Su N, Zheng J, Zhang G, Guan J, Gao X, Cheng Z, Xu C, Xie D, Li Y. Molecular characterization of vascular endothelial growth factor b from spotted sea bass (Lateolabrax maculatus) and its potential roles in decreasing lipid deposition. Int J Biol Macromol 2024; 267:131507. [PMID: 38604419 DOI: 10.1016/j.ijbiomac.2024.131507] [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: 02/06/2024] [Revised: 03/15/2024] [Accepted: 04/08/2024] [Indexed: 04/13/2024]
Abstract
Vascular endothelial growth factor B (VEGFB), a member of the VEGF family, exhibits limited angiogenic activity in mammals but plays an unexpected role in targeting lipids to peripheral tissues. However, its role in lipid metabolism in fish is unknown. In this study, the vegfb gene was cloned and characterized from spotted sea bass (Lateolabrax maculatus). It encodes 254 amino acids and possesses the typical characteristics of the Vegfb family, demonstrating high homology with those from other vertebrate species. The vegfb gene exhibits the highest expression levels in the liver, followed by the gills, intestine, and adipose tissues in spotted sea bass. In vivo, high-lipid diets decreased vegfb expression and increased lipid deposition in liver of fish. In vitro, palmitic acid + oleic acid treatment or vegfb knockdown significantly increased TG and TC contents, promoting lipid droplet deposition in hepatocytes. Vegfb overexpression has the opposite effects, inhibiting lipid deposition and downregulating fatty acid transport and adipogenesis genes. In contrast, the vegfb knockdown significantly upregulated the expression levels of c/ebpα, plin2, and dgat1 (P < 0.05). These results demonstrate that Vegfb may play an important role in reducing lipid deposition by regulating fatty acid transport and adipogenesis in the hepatocytes of spotted sea bass.
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Affiliation(s)
- Ningning Su
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Jun Zheng
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Guanrong Zhang
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Junfeng Guan
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Xin Gao
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Zhiyi Cheng
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Chao Xu
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Dizhi Xie
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China
| | - Yuanyou Li
- College of Marine Science, South China Agricultural University & Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, China.
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15
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Yang K, Li J, Zhu J, Chen Y, He Y, Wang J, Shen K, Wang K, Shi T, Chen W. HOOK3 suppresses proliferation and metastasis in gastric cancer via the SP1/VEGFA axis. Cell Death Discov 2024; 10:33. [PMID: 38228617 DOI: 10.1038/s41420-024-01808-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 12/25/2023] [Accepted: 01/05/2024] [Indexed: 01/18/2024] Open
Abstract
HOOK3, a member of the human hook microtubule-tethering protein family, has been implicated in the progression of cancer. However, the role of HOOK3 in the pathogenesis of gastric cancer (GC) remains incompletely understood. In this study, we investigated the expression of HOOK3 protein in GC tissues using immunohistochemistry (IHC). The findings of our study indicate that the expression levels of HOOK3 in GC tissues were relatively low. Furthermore, a significant negative association was seen between HOOK3 expression and the prognosis of patients with GC. The suppression of HOOK3 resulted in a notable increase in the proliferation, migration, invasion, and survival of GC cells. Conversely, the overexpression of HOOK3 had the opposite impact, reducing these cellular processes. Moreover, in vivo tests have shown evidence that the overexpression of HOOK3 significantly inhibited the formation of tumors and the spread of GC cells to the lungs. In a mechanistic manner, the analysis of RNA-seq data demonstrated that the knockdown of HOOK3 resulted in a notable increase in the expression of vascular endothelial growth factor A (VEGFA) in GC cells. Furthermore, the upregulation of VEGFA counteracted the impacts of HOOK3 upregulation on the proliferation, migration, invasion, and survival of GC cells. Furthermore, it was revealed that specificity protein 1 (SP1) exhibited the ability to bind to the promoter region of VEGFA. Moreover, the overexpression of SP1 successfully counteracted the inhibitory impact of HOOK3 overexpression on the expression of VEGFA in GC cells. In summary, the results of our study indicate that HOOK3 has a role in inhibiting the growth, migration, invasion, and survival of GC cells by modulating the SP1/VEGFA pathway. These findings contribute significant knowledge to our understanding of the underlying mechanisms involved in the development of GC.
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Affiliation(s)
- Kexi Yang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Juntao Li
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jinghan Zhu
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuqi Chen
- Department of Gastroenterology, Dushu Lake Hospital Affiliated of Soochow University, Suzhou, China
| | - Yuxin He
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiayu Wang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Kanger Shen
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Kun Wang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Tongguo Shi
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Weichang Chen
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.
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16
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Zhang S, Tian W, Duan X, Zhang Q, Cao L, Liu C, Li G, Wang Z, Zhang J, Li J, Yang L, Gao Y, Xu Y, Liu J, Yan J, Cui J, Feng L, Liu C, Shen Y, Qi Z. Melatonin attenuates diabetic cardiomyopathy by increasing autophagy of cardiomyocytes via regulation of VEGF-B/GRP78/PERK signaling pathway. Cardiovasc Diabetol 2024; 23:19. [PMID: 38195474 PMCID: PMC10777497 DOI: 10.1186/s12933-023-02078-x] [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: 10/10/2023] [Accepted: 11/27/2023] [Indexed: 01/11/2024] Open
Abstract
AIMS Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel) has been shown to attenuate DCM, however, the underlying mechanism remains unclear. The role of vascular endothelial growth factor-B (VEGF-B) in DCM is little known. In present study, we aimed to investigate whether Mel alleviated DCM via regulation of VEGF-B and explored its underlying mechanisms. METHODS AND RESULTS We found that Mel significantly alleviated cardiac dysfunction and improved autophagy of cardiomyocytes in type 1 diabetes mellitus (T1DM) induced cardiomyopathy mice. VEGF-B was highly expressed in DCM mice in comparison with normal mice, and its expression was markedly reduced after Mel treatment. Mel treatment diminished the interaction of VEGF-B and Glucose-regulated protein 78 (GRP78) and reduced the interaction of GRP78 and protein kinase RNA -like ER kinase (PERK). Furthermore, Mel increased phosphorylation of PERK and eIF2α, then up-regulated the expression of ATF4. VEGF-B-/- mice imitated the effect of Mel on wild type diabetic mice. Interestingly, injection with Recombinant adeno-associated virus serotype 9 (AAV9)-VEGF-B or administration of GSK2656157 (GSK), an inhibitor of phosphorylated PERK abolished the protective effect of Mel on DCM. Furthermore, rapamycin, an autophagy agonist displayed similar effect with Mel treatment; while 3-Methyladenine (3-MA), an autophagy inhibitor neutralized the effect of Mel on high glucose-treated neonatal rat ventricular myocytes. CONCLUSIONS These results demonstrated that Mel attenuated DCM via increasing autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway.
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Affiliation(s)
- Shengzheng Zhang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Wencong Tian
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300000, China
| | - Xianxian Duan
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Qian Zhang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Lei Cao
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300000, China
| | - Chunlei Liu
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Guangru Li
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Ziwei Wang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Junwei Zhang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Jing Li
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Liang Yang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300000, China
| | - Yang Gao
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300000, China
| | - Yang Xu
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Jie Liu
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Jie Yan
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Jianlin Cui
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Lifeng Feng
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Chang Liu
- School of Medical Technology, Tianjin Medical University, Tianjin, 300203, China
- Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, 571199, China
| | - Yanna Shen
- School of Medical Technology, Tianjin Medical University, Tianjin, 300203, China.
- Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, 571199, China.
| | - Zhi Qi
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China.
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300000, China.
- Xinjiang Production and Construction Corps Hospital, Xinjiang, 830092, China.
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17
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Hellsten Y, Gliemann L. Peripheral limitations for performance: Muscle capillarization. Scand J Med Sci Sports 2024; 34:e14442. [PMID: 37770233 DOI: 10.1111/sms.14442] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 10/03/2023]
Abstract
Sufficient delivery of oxygen and metabolic substrates, together with removal of waste products, are key elements of muscle performance. Capillaries are the primary site for this exchange in skeletal muscle and the degree of muscle capillarization affects diffusion conditions by influencing mean transit time, capillary surface area and diffusion distance. Muscle capillarization may thus represent a limiting factor for performance. Exercise training increases the number of capillaries per muscle fiber by about 10%-20% within a few weeks in untrained subjects, whereas capillary growth progresses more slowly in well-trained endurance athletes. Studies show that capillaries are tortuous, situated along and across the length of the fibers with an arrangement related to muscle fascicles. Although direct data is lacking, it is possible that years of training not only enhances capillary density but also optimizes the positioning of capillaries, to further improve the diffusion conditions. Muscle capillarization has been shown to increase oxygen extraction during exercise in humans, but direct evidence for a causal link between increased muscle capillarization and performance is scarce. This review covers current knowledge on the implications of muscle capillarization for oxygen and glucose uptake as well as performance. A brief overview of the process of capillary growth and of physical factors, inherent to exercise, which promote angiogenesis, provides the foundation for a discussion on how different training modalities may influence muscle capillary growth. Finally, we identify three areas for future research on the role of capillarization for exercise performance.
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Affiliation(s)
- Ylva Hellsten
- The August Krogh Section for Human Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Lasse Gliemann
- The August Krogh Section for Human Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
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Pérez-Gutiérrez L, Ferrara N. Biology and therapeutic targeting of vascular endothelial growth factor A. Nat Rev Mol Cell Biol 2023; 24:816-834. [PMID: 37491579 DOI: 10.1038/s41580-023-00631-w] [Citation(s) in RCA: 149] [Impact Index Per Article: 74.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/16/2023] [Indexed: 07/27/2023]
Abstract
The formation of new blood vessels, called angiogenesis, is an essential pathophysiological process in which several families of regulators have been implicated. Among these, vascular endothelial growth factor A (VEGFA; also known as VEGF) and its two tyrosine kinase receptors, VEGFR1 and VEGFR2, represent a key signalling pathway mediating physiological angiogenesis and are also major therapeutic targets. VEGFA is a member of the gene family that includes VEGFB, VEGFC, VEGFD and placental growth factor (PLGF). Three decades after its initial isolation and cloning, VEGFA is arguably the most extensively investigated signalling system in angiogenesis. Although many mediators of angiogenesis have been identified, including members of the FGF family, angiopoietins, TGFβ and sphingosine 1-phosphate, all current FDA-approved anti-angiogenic drugs target the VEGF pathway. Anti-VEGF agents are widely used in oncology and, in combination with chemotherapy or immunotherapy, are now the standard of care in multiple malignancies. Anti-VEGF drugs have also revolutionized the treatment of neovascular eye disorders such as age-related macular degeneration and ischaemic retinal disorders. In this Review, we emphasize the molecular, structural and cellular basis of VEGFA action as well as recent findings illustrating unexpected interactions with other pathways and provocative reports on the role of VEGFA in regenerative medicine. We also discuss clinical and translational aspects of VEGFA. Given the crucial role that VEGFA plays in regulating angiogenesis in health and disease, this molecule is largely the focus of this Review.
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Affiliation(s)
- Lorena Pérez-Gutiérrez
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Napoleone Ferrara
- Department of Pathology, University of California San Diego, La Jolla, CA, USA.
- Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
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19
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Yang Y, Zhong J, Cui D, Jensen LD. Up-to-date molecular medicine strategies for management of ocular surface neovascularization. Adv Drug Deliv Rev 2023; 201:115084. [PMID: 37689278 DOI: 10.1016/j.addr.2023.115084] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/30/2023] [Accepted: 09/04/2023] [Indexed: 09/11/2023]
Abstract
Ocular surface neovascularization and its resulting pathological changes significantly alter corneal refraction and obstruct the light path to the retina, and hence is a major cause of vision loss. Various factors such as infection, irritation, trauma, dry eye, and ocular surface surgery trigger neovascularization via angiogenesis and lymphangiogenesis dependent on VEGF-related and alternative mechanisms. Recent advances in antiangiogenic drugs, nanotechnology, gene therapy, surgical equipment and techniques, animal models, and drug delivery strategies have provided a range of novel therapeutic options for the treatment of ocular surface neovascularization. In this review article, we comprehensively discuss the etiology and mechanisms of corneal neovascularization and other types of ocular surface neovascularization, as well as emerging animal models and drug delivery strategies that facilitate its management.
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Affiliation(s)
- Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Junmu Zhong
- Department of Ophthalmology, Longyan First Hospital Affiliated to Fujian Medical University, Longyan 364000, Fujian Province, China
| | - Dongmei Cui
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen 518040, Guangdong Province, China
| | - Lasse D Jensen
- Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine, Unit of Cardiovascular Medicine, Linköping University, Linköping, Sweden.
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20
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Rauniyar K, Bokharaie H, Jeltsch M. Expansion and collapse of VEGF diversity in major clades of the animal kingdom. Angiogenesis 2023; 26:437-461. [PMID: 37017884 PMCID: PMC10328876 DOI: 10.1007/s10456-023-09874-9] [Citation(s) in RCA: 6] [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: 01/20/2023] [Accepted: 03/17/2023] [Indexed: 04/06/2023]
Abstract
Together with the platelet-derived growth factors (PDGFs), the vascular endothelial growth factors (VEGFs) form the PDGF/VEGF subgroup among cystine knot growth factors. The evolutionary relationships within this subgroup have not been examined thoroughly to date. Here, we comprehensively analyze the PDGF/VEGF growth factors throughout all animal phyla and propose a phylogenetic tree. Vertebrate whole-genome duplications play a role in expanding PDGF/VEGF diversity, but several limited duplications are necessary to account for the temporal pattern of emergence. The phylogenetically oldest PDGF/VEGF-like growth factor likely featured a C-terminus with a BR3P signature, a hallmark of the modern-day lymphangiogenic growth factors VEGF-C and VEGF-D. Some younger VEGF genes, such as VEGFB and PGF, appeared completely absent in important vertebrate clades such as birds and amphibia, respectively. In contrast, individual PDGF/VEGF gene duplications frequently occurred in fish on top of the known fish-specific whole-genome duplications. The lack of precise counterparts for human genes poses limitations but also offers opportunities for research using organisms that diverge considerably from humans. Sources for the graphical abstract: 326 MYA and older [1]; 72-240 MYA [2]; 235-65 MYA [3].
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Affiliation(s)
- Khushbu Rauniyar
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Biocenter 2, (Viikinkaari 5E), P.O. Box. 56, 00790, Helsinki, Finland
| | - Honey Bokharaie
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Biocenter 2, (Viikinkaari 5E), P.O. Box. 56, 00790, Helsinki, Finland
| | - Michael Jeltsch
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Biocenter 2, (Viikinkaari 5E), P.O. Box. 56, 00790, Helsinki, Finland.
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Wihuri Research Institute, Helsinki, Finland.
- Helsinki One Health, University of Helsinki, Helsinki, Finland.
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21
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Mendoza-Torreblanca JG, Cárdenas-Rodríguez N, Carro-Rodríguez J, Contreras-García IJ, Garciadiego-Cázares D, Ortega-Cuellar D, Martínez-López V, Alfaro-Rodríguez A, Evia-Ramírez AN, Ignacio-Mejía I, Vargas-Hernández MA, Bandala C. Antiangiogenic Effect of Dopamine and Dopaminergic Agonists as an Adjuvant Therapeutic Option in the Treatment of Cancer, Endometriosis, and Osteoarthritis. Int J Mol Sci 2023; 24:10199. [PMID: 37373348 DOI: 10.3390/ijms241210199] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/12/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Dopamine (DA) and dopamine agonists (DA-Ag) have shown antiangiogenic potential through the vascular endothelial growth factor (VEGF) pathway. They inhibit VEGF and VEGF receptor 2 (VEGFR 2) functions through the dopamine receptor D2 (D2R), preventing important angiogenesis-related processes such as proliferation, migration, and vascular permeability. However, few studies have demonstrated the antiangiogenic mechanism and efficacy of DA and DA-Ag in diseases such as cancer, endometriosis, and osteoarthritis (OA). Therefore, the objective of this review was to describe the mechanisms of the antiangiogenic action of the DA-D2R/VEGF-VEGFR 2 system and to compile related findings from experimental studies and clinical trials on cancer, endometriosis, and OA. Advanced searches were performed in PubMed, Web of Science, SciFinder, ProQuest, EBSCO, Scopus, Science Direct, Google Scholar, PubChem, NCBI Bookshelf, DrugBank, livertox, and Clinical Trials. Articles explaining the antiangiogenic effect of DA and DA-Ag in research articles, meta-analyses, books, reviews, databases, and clinical trials were considered. DA and DA-Ag have an antiangiogenic effect that could reinforce the treatment of diseases that do not yet have a fully curative treatment, such as cancer, endometriosis, and OA. In addition, DA and DA-Ag could present advantages over other angiogenic inhibitors, such as monoclonal antibodies.
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Affiliation(s)
| | - Noemi Cárdenas-Rodríguez
- Laboratorio de Neurociencias, Subdirección de Medicina Experimental, Instituto Nacional de Pediatría, Mexico City 04530, Mexico
| | - Jazmín Carro-Rodríguez
- Laboratorio de Medicina Traslacional Aplicada a Neurociencias, Enfermedades Crónicas y Emergentes, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Itzel Jatziri Contreras-García
- Laboratorio de Biología de la Reproducción, Subdirección de Medicina Experimental, Instituto Nacional de Pediatría, Mexico City 04530, Mexico
| | - David Garciadiego-Cázares
- Unidad de Ingeniería de Tejidos, Terapia Celular y Medicina Regenerativa, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
| | - Daniel Ortega-Cuellar
- Laboratorio Nutrición Experimental, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico
| | - Valentín Martínez-López
- Unidad de Ingeniería de Tejidos, Terapia Celular y Medicina Regenerativa, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
| | - Alfonso Alfaro-Rodríguez
- Neurociencias Básicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Secretaría de Salud, Mexico City 14389, Mexico
| | - Alberto Nayib Evia-Ramírez
- Servicio de Reconstrucción Articular, Cadera y Rodilla, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
| | - Iván Ignacio-Mejía
- Laboratorio de Medicina Traslacional, Escuela Militar de Graduados de Sanidad, Mexico City 11200, Mexico
| | | | - Cindy Bandala
- Laboratorio de Medicina Traslacional Aplicada a Neurociencias, Enfermedades Crónicas y Emergentes, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico
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22
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Falkevall A, Mehlem A, Folestad E, Ning FC, Osorio-Conles Ó, Radmann R, de Hollanda A, Wright SD, Scotney P, Nash A, Eriksson U. Inhibition of VEGF-B signaling prevents non-alcoholic fatty liver disease development by targeting lipolysis in the white adipose tissue. J Hepatol 2023; 78:901-913. [PMID: 36717026 DOI: 10.1016/j.jhep.2023.01.014] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 12/22/2022] [Accepted: 01/13/2023] [Indexed: 01/30/2023]
Abstract
BACKGROUND & AIMS Hepatic steatosis is a hallmark of non-alcoholic fatty liver disease (NAFLD), a common comorbidity in type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD is complex and involves the crosstalk between the liver and the white adipose tissue (WAT). Vascular endothelial growth factor B (VEGF-B) has been shown to control tissue lipid accumulation by regulating the transport properties of the vasculature. The role of VEGF-B signaling and the contribution to hepatic steatosis and NAFLD in T2DM is currently not understood. METHODS C57BL/6 J mice treated with a neutralizing antibody against VEGF-B, or mice with adipocyte-specific overexpression or under-expression of VEGF-B (AdipoqCre+/VEGF-BTG/+ mice and AdipoqCre+/Vegfbfl/+mice) were subjected to a 6-month high-fat diet (HFD), or chow-diet, whereafter NAFLD development was assessed. VEGF-B expression was analysed in WAT biopsies from patients with obesity and NAFLD in a pre-existing clinical cohort (n = 24 patients with NAFLD and n = 24 without NAFLD) and correlated to clinicopathological features. RESULTS Pharmacological inhibition of VEGF-B signaling in diabetic mice reduced hepatic steatosis and NAFLD by blocking WAT lipolysis. Mechanistically we show, by using HFD-fed AdipoqCre+/VEGF-BTG/+ mice and HFD-fed AdipoqCre+/Vegfbfl/+mice, that inhibition of VEGF-B signaling targets lipolysis in adipocytes. Reducing VEGF-B signaling ameliorated NAFLD by decreasing WAT inflammation, resolving WAT insulin resistance, and lowering the activity of the hormone sensitive lipase. Analyses of human WAT biopsies from individuals with NAFLD provided evidence supporting the contribution of VEGF-B signaling to NAFLD development. VEGF-B expression levels in adipocytes from two WAT depots correlated with development of dysfunctional WAT and NAFLD in humans. CONCLUSIONS Taken together, our data from mouse models and humans suggest that VEGF-B antagonism may represent an approach to combat NAFLD by targeting hepatic steatosis through suppression of lipolysis. IMPACT AND IMPLICATIONS Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity in type 2 diabetes mellitus (T2DM) and has a global prevalence of between 25-29%. There are currently no approved drugs for NAFLD, and given the scale of the ongoing diabetes epidemics, there is an urgent need to identify new treatment options. Our work suggests that VEGF-B antagonism may represent an approach to combat NAFLD by targeting hepatic steatosis through suppression of lipolysis. The neutralizing anti-VEGF-B antibody, which was used in this study, has already entered clinical trials for patients with diabetes. Therefore, we believe that our results are of great general interest to a broad audience, including patients and patient organizations, the medical community, academia, the life science industry and the public.
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Affiliation(s)
- Annelie Falkevall
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Annika Mehlem
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Erika Folestad
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Frank Chenfei Ning
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Óscar Osorio-Conles
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Rosa Radmann
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Ana de Hollanda
- Obesity Unit. Clinical Hospital of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red Fisiopatologia de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain
| | | | | | - Andrew Nash
- CSL Innovation Pty Ltd, Parkville, Victoria, Australia
| | - Ulf Eriksson
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
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23
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Gu L, Wang Z, Gu H, Wang H, Liu L, Zhang WB. Atf4 regulates angiogenic differences between alveolar bone and long bone macrophages by regulating M1 polarization, based on single-cell RNA sequencing, RNA-seq and ATAC-seq analysis. J Transl Med 2023; 21:193. [PMID: 36918894 PMCID: PMC10012539 DOI: 10.1186/s12967-023-04046-1] [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: 12/04/2022] [Accepted: 03/08/2023] [Indexed: 03/15/2023] Open
Abstract
In the repair of maxillofacial bone defects, autogenous craniofacial bone can often provide superior clinical results over long bone grafts. Most current studies have focused on the osteogenic differences between alveolar bone marrow (ABM) and long bone marrow (LBM), however, studies about the angiogenic differences between the two are currently lacking. We downloaded single-cell RNA sequencing (scRNA-seq) of mouse ABM and LBM respectively from the public database, and the data were processed by using Seurat package. CellphoneDB2 results showed that macrophages had the strongest interaction with mesenchymal stem cells (MSCs) and endothelial cells (ECs). ELISA results confirmed that ABM macrophages secreted a higher level of vascular endothelial growth factor A (Vegfa) compared to LBM macrophages, which further promoted angiogenesis of ECs and MSCs. Using SCENIC package, six key transcription factors (TFs) were identified to regulate the difference between ABM and LBM macrophages, and activating transcription factor 4 (Atf4) was confirmed to be more expressed in ABM macrophages by polymerase chain reaction (PCR) and western blot (WB), with predicted target genes including Vegfa. Besides, the result of scRNA-seq implied ABM macrophages more in M1 status than LBM macrophages, which was confirmed by the following experiments. From the results of another assay for transposase accessible chromatin sequencing (ATAC-seq) and RNA-seq about M1 macrophages, Atf4 was also confirmed to regulate the M1 polarization. So, we suspected that Atf4 regulated the different expression of Vegfa between ABM and LBM macrophages by activating M1 polarization. After knocking down Atf4, the expression of M1 polarization markers and Vegfa were downregulated and vasculogenic differences were eliminated, which were subsequently reversed by the addition of LPS/IFN-γ. Our study might provide a new idea to improve the success rate of autologous bone grafting and treatment of oral diseases.
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Affiliation(s)
- Lanxin Gu
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China
| | - Zhongyuan Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Hong Gu
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210029, China
| | - Hua Wang
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, 210029, China.
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China.
| | - Luwei Liu
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, 210029, China.
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China.
| | - Wei-Bing Zhang
- Department of Stomatology, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, China.
- Department of Stomatology, Medical Center of Soochow University, Suzhou, China.
- Department of Stomatology, Suzhou Dushu Lake Hospital, Suzhou, China.
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24
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Tumor Vasculature as an Emerging Pharmacological Target to Promote Anti-Tumor Immunity. Int J Mol Sci 2023; 24:ijms24054422. [PMID: 36901858 PMCID: PMC10002465 DOI: 10.3390/ijms24054422] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/20/2023] [Accepted: 02/22/2023] [Indexed: 02/25/2023] Open
Abstract
Tumor vasculature abnormality creates a microenvironment that is not suitable for anti-tumor immune response and thereby induces resistance to immunotherapy. Remodeling of dysfunctional tumor blood vessels by anti-angiogenic approaches, known as vascular normalization, reshapes the tumor microenvironment toward an immune-favorable one and improves the effectiveness of immunotherapy. The tumor vasculature serves as a potential pharmacological target with the capacity of promoting an anti-tumor immune response. In this review, the molecular mechanisms involved in tumor vascular microenvironment-modulated immune reactions are summarized. In addition, the evidence of pre-clinical and clinical studies for the combined targeting of pro-angiogenic signaling and immune checkpoint molecules with therapeutic potential are highlighted. The heterogeneity of endothelial cells in tumors that regulate tissue-specific immune responses is also discussed. The crosstalk between tumor endothelial cells and immune cells in individual tissues is postulated to have a unique molecular signature and may be considered as a potential target for the development of new immunotherapeutic approaches.
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25
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Yang Y, Cao Y. The impact of VEGF on cancer metastasis and systemic disease. Semin Cancer Biol 2022; 86:251-261. [PMID: 35307547 DOI: 10.1016/j.semcancer.2022.03.011] [Citation(s) in RCA: 135] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/08/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023]
Abstract
Metastasis is the leading cause of cancer-associated mortality and the underlying mechanisms of cancer metastasis remain elusive. Both blood and lymphatic vasculatures are essential structures for mediating distal metastasis. The vasculature plays multiple functions, including accelerating tumor growth, sustaining the tumor microenvironment, supplying growth and invasive signals, promoting metastasis, and causing cancer-associated systemic disease. VEGF is one of the key angiogenic factors in tumors and participates in the initial stage of tumor development, progression and metastasis. Consequently, VEGF and its receptor-mediated signaling pathways have become one of the most important therapeutic targets for treating various cancers. Today, anti-VEGF-based antiangiogenic drugs (AADs) are widely used in the clinic for treating different types of cancer in human patients. Despite nearly 20-year clinical experience with AADs, the impact of these drugs on cancer metastasis and systemic disease remains largely unknown. In this review article, we focus our discussion on tumor VEGF in cancer metastasis and systemic disease and mechanisms underlying AADs in clinical benefits.
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Affiliation(s)
- Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institute, 171 77 Stockholm, Sweden.
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26
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Li R, Li Y, Yang X, Hu Y, Yu H, Li Y. Reducing VEGFB accelerates NAFLD and insulin resistance in mice via inhibiting AMPK signaling pathway. J Transl Med 2022; 20:341. [PMID: 35907871 PMCID: PMC9338666 DOI: 10.1186/s12967-022-03540-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 07/15/2022] [Indexed: 11/10/2022] Open
Abstract
Objective Vascular endothelial growth factor B (VEGFB) was regarded to improve lipid metabolism and reduce obesity-related hyperlipidemia. Whether VEGFB participates in lipid metabolism in nonalcoholic fatty liver disease (NAFLD) has not been clear yet. This study investigated the involvement of VEGFB in lipid metabolism and insulin resistance via the AMPK signaling pathway in NAFLD. Methods We constructed the animal and cell model of NAFLD after VEGFB gene knockout to detect liver damage and metabolism in NAFLD. Bioinformatics analysis of VEGFB and the AMPK signaling pathway relative genes to verify the differential proteins. And mRNA levels of NAFLD fatty acid metabolism-related genes were detected. Results After the systemic VEGFB knockout mice were fed with high fat, the body fat, serum lipoprotein, NAFLD score, and insulin resistance were increased. Animal and cell experiments showed that the expression levels of phosphorylated proteins of CaMKK2 and AMPK decreased, the expression of proteins related to AMPK/ACC/CPT1 signaling pathway decreased, and the target genes CPT1α and Lcad decreased accordingly, reducing fatty acid oxidation in hepatocyte mitochondria; The expression of AMPK/SREBP1/Scd1 signaling pathway relative proteins increased, ACC1 and FAS increased correspondingly, which increased lipid synthesis in the endoplasmic reticulum. Conclusion VEGFB can participate in lipid metabolism and insulin resistance of NAFLD through the AMPK signaling pathway. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03540-2.
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Affiliation(s)
- Rongrong Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, 264000, Shandong, China
| | - Yuqi Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, 264000, Shandong, China
| | - Xueling Yang
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, 264000, Shandong, China
| | - Yaorui Hu
- Department of Anatomy, School of Basic Medicine, Binzhou Medical University, Yantai, 264000, Shandong, China
| | - Haining Yu
- Stomatology Department, Stomatological College, Binzhou Medical University, Yantai, 264000, Shandong, China
| | - Yana Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, 264000, Shandong, China.
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27
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Angiogenesis, Lymphangiogenesis, and Inflammation in Chronic Obstructive Pulmonary Disease (COPD): Few Certainties and Many Outstanding Questions. Cells 2022; 11:cells11101720. [PMID: 35626756 PMCID: PMC9139415 DOI: 10.3390/cells11101720] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 05/20/2022] [Accepted: 05/21/2022] [Indexed: 02/07/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation, predominantly affecting the lung parenchyma and peripheral airways, that results in progressive and irreversible airflow obstruction. COPD development is promoted by persistent pulmonary inflammation in response to several stimuli (e.g., cigarette smoke, bacterial and viral infections, air pollution, etc.). Angiogenesis, the formation of new blood vessels, and lymphangiogenesis, the formation of new lymphatic vessels, are features of airway inflammation in COPD. There is compelling evidence that effector cells of inflammation (lung-resident macrophages and mast cells and infiltrating neutrophils, eosinophils, basophils, lymphocytes, etc.) are major sources of a vast array of angiogenic (e.g., vascular endothelial growth factor-A (VEGF-A), angiopoietins) and/or lymphangiogenic factors (VEGF-C, -D). Further, structural cells, including bronchial and alveolar epithelial cells, endothelial cells, fibroblasts/myofibroblasts, and airway smooth muscle cells, can contribute to inflammation and angiogenesis in COPD. Although there is evidence that alterations of angiogenesis and, to a lesser extent, lymphangiogenesis, are associated with COPD, there are still many unanswered questions.
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28
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Mao Y, Meng L, Liu H, Lu Y, Yang K, Ouyang G, Ban Y, Chen S. Therapeutic potential of traditional Chinese medicine for vascular endothelial growth factor. J Zhejiang Univ Sci B 2022; 23:353-364. [PMID: 35557037 DOI: 10.1631/jzus.b2101055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Vascular endothelial growth factor (VEGF) is the main regulator of physiological angiogenesis during embryonic development, bone growth, and reproductive function, and it also participates in a series of pathological changes. Traditional Chinese medicine (TCM), with a history of more than 2000 years, has been widely used in clinical practice, while the exploration of its mechanisms has only begun. This review summarizes the research of recent years on the influence of TCM on VEGF. It is found that many Chinese medicines and recipes have a regulatory effect on VEGF, indicating that Chinese medicine has broad prospects as a complementary and alternative therapy, providing new treatment ideas for clinical applications and the theoretical basis for research on the mechanisms of TCM.
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Affiliation(s)
- Yijia Mao
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301608, China
| | - Lingkai Meng
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301608, China
| | - Huayi Liu
- Department of Digestive Diseases, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin 300120, China.
| | - Yuting Lu
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301608, China
| | - Kuo Yang
- Department of Digestive Diseases, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin 300120, China
| | - Guangze Ouyang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301608, China
| | - Yanran Ban
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301608, China
| | - Shuang Chen
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301608, China
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Makkeyah SM, Elseedawy ME, Abdel-Kader HM, Mokhtar GM, Ragab IA. Vascular endothelial growth factor response with propranolol therapy in patients with infantile hemangioma. Pediatr Hematol Oncol 2022; 39:215-224. [PMID: 34477031 DOI: 10.1080/08880018.2021.1961956] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Vascular endothelial growth factor-A (VEGF-A) is a master regulator of angiogenesis, with higher levels in infantile hemangioma (IH). The effects of propranolol on IH are not fully understood and may involve vasoconstriction, angiogenesis inhibition, and apoptosis induction. Therefore, we examined the effects of propranolol therapy on levels of VEGF-A in patients with IH in the proliferative phase and compared the VEGF-A levels to those in untreated patients in the involuting or involuted phases, as well as studied the consistency between the clinical and VEGF responses in patients receiving treatment. In a prospective study, we compared 24 patients with IH in the proliferative phase to 9 patients with IH in the involuting or involuted phase, assessing clinical responses to therapy and changes in VEGF-A levels after 3 months. The median VEGF level before treatment was 275 pg/ml; however, after 3 months, the level significantly decreased to 100 pg/ml (P = 0.007). Median VEGF was significantly higher in patients in the proliferative phase after 3 months of treatment (100 pg/ml) as compared to those in the involuting phase (50 pg/ml). We found no significant correlation between VEGF level and IH size reduction. Propranolol therapy induced a significant decline in VEGF levels at the 3-month evaluation in patients in the proliferative phase; however, this did not reach the levels of IH in the involuting phase. VEGF response was not translated to a clinical response in some patients with IH. These results put in uncertainty the clinical benefit of targeting VEGF pathway in IH.
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Affiliation(s)
- S M Makkeyah
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - M E Elseedawy
- bDepartment of Pediatric Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - H M Abdel-Kader
- bDepartment of Pediatric Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - G M Mokhtar
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - I A Ragab
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Eldrid C, Zloh M, Fotinou C, Yelland T, Yu L, Mota F, Selwood DL, Djordjevic S. VEGFA, B, C: Implications of the C-Terminal Sequence Variations for the Interaction with Neuropilins. Biomolecules 2022; 12:biom12030372. [PMID: 35327564 PMCID: PMC8945599 DOI: 10.3390/biom12030372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 11/23/2022] Open
Abstract
Vascular endothelial growth factors (VEGFs) are the key regulators of blood and lymphatic vessels’ formation and function. Each of the proteins from the homologous family VEGFA, VEGFB, VEGFC and VEGFD employs a core cysteine-knot structural domain for the specific interaction with one or more of the cognate tyrosine kinase receptors. Additional diversity is exhibited by the involvement of neuropilins–transmembrane co-receptors, whose b1 domain contains the binding site for the C-terminal sequence of VEGFs. Although all relevant isoforms of VEGFs that interact with neuropilins contain the required C-terminal Arg residue, there is selectivity of neuropilins and VEGF receptors for the VEGF proteins, which is reflected in the physiological roles that they mediate. To decipher the contribution made by the C-terminal sequences of the individual VEGF proteins to that functional differentiation, we determined structures of molecular complexes of neuropilins and VEGF-derived peptides and examined binding interactions for all neuropilin-VEGF pairs experimentally and computationally. While X-ray crystal structures and ligand-binding experiments highlighted similarities between the ligands, the molecular dynamics simulations uncovered conformational preferences of VEGF-derived peptides beyond the C-terminal arginine that contribute to the ligand selectivity of neuropilins. The implications for the design of the selective antagonists of neuropilins’ functions are discussed.
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Affiliation(s)
- Charles Eldrid
- Structural and Molecular Biology, ISMB, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK; (C.E.); (C.F.); (T.Y.); (L.Y.)
| | - Mire Zloh
- UCL School of Pharmacy, University College London, London WC1N 1AX, UK;
- Faculty of Pharmacy, University Business Academy, 2100 Novi Sad, Serbia
| | - Constantina Fotinou
- Structural and Molecular Biology, ISMB, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK; (C.E.); (C.F.); (T.Y.); (L.Y.)
| | - Tamas Yelland
- Structural and Molecular Biology, ISMB, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK; (C.E.); (C.F.); (T.Y.); (L.Y.)
| | - Lefan Yu
- Structural and Molecular Biology, ISMB, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK; (C.E.); (C.F.); (T.Y.); (L.Y.)
| | - Filipa Mota
- Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK; (F.M.); (D.L.S.)
| | - David L. Selwood
- Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK; (F.M.); (D.L.S.)
| | - Snezana Djordjevic
- Structural and Molecular Biology, ISMB, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK; (C.E.); (C.F.); (T.Y.); (L.Y.)
- Correspondence: ; Tel.: +44-(0)20-7679-2230
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Ling M, Quan L, Lai X, Lang L, Li F, Yang X, Fu Y, Feng S, Yi X, Zhu C, Gao P, Zhu X, Wang L, Shu G, Jiang Q, Wang S. VEGFB Promotes Myoblasts Proliferation and Differentiation through VEGFR1-PI3K/Akt Signaling Pathway. Int J Mol Sci 2021; 22:13352. [PMID: 34948148 PMCID: PMC8707860 DOI: 10.3390/ijms222413352] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/05/2021] [Accepted: 12/09/2021] [Indexed: 01/06/2023] Open
Abstract
It has been demonstrated that vascular endothelial growth factor B (VEGFB) plays a vital role in regulating vascular biological function. However, the role of VEGFB in regulating skeletal muscle cell proliferation and differentiation remains unclear. Thus, this study aimed to investigate the effects of VEGFB on C2C12 myoblast proliferation and differentiation and to explore the underlying mechanism. For proliferation, VEGFB significantly promoted the proliferation of C2C12 myoblasts with the upregulating expression of cyclin D1 and PCNA. Meanwhile, VEGFB enhanced vascular endothelial growth factor receptor 1 (VEGFR1) expression and activated the PI3K/Akt signaling pathway in a VEGFR1-dependent manner. In addition, the knockdown of VEGFR1 and inhibition of PI3K/Akt totally abolished the promotion of C2C12 proliferation induced by VEGFB, suggesting that VEGFB promoted C2C12 myoblast proliferation through the VEGFR1-PI3K/Akt signaling pathway. Regarding differentiation, VEGFB significantly stimulated the differentiation of C2C12 myoblasts via VEGFR, with elevated expressions of MyoG and MyHC. Furthermore, the knockdown of VEGFR1 rather than NRP1 eliminated the VEGFB-stimulated C2C12 differentiation. Moreover, VEGFB activated the PI3K/Akt/mTOR signaling pathway in a VEGFR1-dependent manner. However, the inhibition of PI3K/Akt/mTOR blocked the promotion of C2C12 myoblasts differentiation induced by VEGFB, indicating the involvement of the PI3K/Akt pathway. To conclude, these findings showed that VEGFB promoted C2C12 myoblast proliferation and differentiation via the VEGFR1-PI3K/Akt signaling pathway, providing new insights into the regulation of skeletal muscle development.
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Affiliation(s)
- Mingfa Ling
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Lulu Quan
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Xumin Lai
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Limin Lang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Fan Li
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Xiaohua Yang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Yiming Fu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Shengchun Feng
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Xin Yi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Canjun Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Ping Gao
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Xiaotong Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Lina Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Gang Shu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
| | - Songbo Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (M.L.); (L.Q.); (X.L.); (L.L.); (F.L.); (X.Y.); (Y.F.); (S.F.); (X.Y.); (C.Z.); (P.G.); (X.Z.); (L.W.); (G.S.); (Q.J.)
- National Engineering Research Center for the Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
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Gao J, Xu G, Xu P. Whole-genome resequencing of three Coilia nasus population reveals genetic variations in genes related to immune, vision, migration, and osmoregulation. BMC Genomics 2021; 22:878. [PMID: 34872488 PMCID: PMC8647404 DOI: 10.1186/s12864-021-08182-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 11/17/2021] [Indexed: 11/17/2022] Open
Abstract
Background Coilia nasus is an important anadromous fish, widely distributed in China, Japan, and Korea. Based on morphological and ecological researches of C. nasus, two ecotypes were identified. One is the anadromous population (AP). The sexually mature fish run thousands of kilometers from marine to river for spawning. Another one is the resident population which cannot migrate. Based on their different habitats, they were classified into landlocked population (LP) and sea population (SP) which were resident in the freshwater lake and marine during the entire lifetime, respectively. However, they have never been systematically studied. Moreover, C. nasus is declining sharply due to overfishing and pollution recently. Therefore, further understandings of C. nasus populations are needed for germplasm protection. Results Whole-genome resequencing of AP, LP, and SP were performed to enrich the understanding of different populations of C. nasus. At the genome level, 3,176,204, 3,307,069, and 3,207,906 single nucleotide polymorphisms (SNPs) and 1,892,068, 2,002,912, and 1,922,168 insertion/deletion polymorphisms (InDels) were generated in AP, LP, and SP, respectively. Selective sweeping analysis showed that 1022 genes were selected in AP vs LP; 983 genes were selected in LP vs SP; 116 genes were selected in AP vs SP. Among them, selected genes related to immune, vision, migration, and osmoregulation were identified. Furthermore, their expression profiles were detected by quantitative real-time PCR. Expression levels of selected genes related to immune, and vision in LP were significantly lower than AP and SP. Selected genes related to migration in AP were expressed significantly more highly than LP. Expression levels of selected genes related to osmoregulation were also detected. The expression of NKAα and NKCC1 in LP were significantly lower than SP, while expression of NCC, SLC4A4, NHE3, and V-ATPase in LP was significantly higher than SP. Conclusions Combined to life history of C. nasus populations, our results revealed that the molecular mechanisms of their differences of immune, vision, migration, and osmoregulation. Our findings will provide a further understanding of different populations of C. nasus and will be beneficial for wild C. nasus protection. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-021-08182-0.
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Affiliation(s)
- Jun Gao
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, Jiangsu, China
| | - Gangchun Xu
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, Jiangsu, China. .,Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, Jiangsu, China.
| | - Pao Xu
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, Jiangsu, China. .,Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, Jiangsu, China.
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Shang R, Lal N, Lee CS, Zhai Y, Puri K, Seira O, Boushel RC, Sultan I, Räsänen M, Alitalo K, Hussein B, Rodrigues B. Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart. Am J Physiol Endocrinol Metab 2021; 321:E753-E765. [PMID: 34747201 DOI: 10.1152/ajpendo.00219.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cardiac muscle uses multiple sources of energy including glucose and fatty acid (FA). The heart cannot synthesize FA and relies on obtaining it from other sources, with lipoprotein lipase (LPL) breakdown of lipoproteins suggested to be a key source of FA for cardiac use. Recent work has indicated that cardiac vascular endothelial growth factor B (VEGFB) overexpression expands the coronary vasculature and facilitates metabolic reprogramming that favors glucose utilization. We wanted to explore whether this influence of VEGFB on cardiac metabolism involves regulation of LPL activity with consequent effects on lipotoxicity and insulin signaling. The transcriptomes of rats with and without cardiomyocyte-specific overexpression of human VEGFB were compared by using RNA sequencing. Isolated perfused hearts or cardiomyocytes incubated with heparin were used to enable measurement of LPL activity. Untargeted metabolomic analysis was performed for quantification of cardiac lipid metabolites. Cardiac insulin sensitivity was evaluated using fast-acting insulin. Isolated heart and cardiomyocytes were used to determine transgene-encoded VEGFB isoform secretion patterns and mitochondrial oxidative capacity using high-resolution respirometry and extracellular flux analysis. In vitro, transgenic cardiomyocytes incubated overnight and thus exposed to abundantly secreted VEGFB isoforms, in the absence of any in vivo confounding regulators of cardiac metabolism, demonstrated higher basal oxygen consumption. In the whole heart, VEGFB overexpression induced an angiogenic response that was accompanied by limited cardiac LPL activity through multiple mechanisms. This was associated with a lowered accumulation of lipid intermediates, diacylglycerols and lysophosphatidylcholine, that are known to influence insulin action. In response to exogenous insulin, transgenic hearts demonstrated increased insulin sensitivity. In conclusion, the interrogation of VEGFB function on cardiac metabolism uncovered an intriguing and previously unappreciated effect to lower LPL activity and prevent lipid metabolite accumulation to improve insulin action. VEGFB could be a potential cardioprotective therapy to treat metabolic disorders, for example, diabetes.NEW & NOTEWORTHY In hearts overexpressing vascular endothelial growth factor B (VEGFB), besides its known angiogenic response, multiple regulatory mechanisms lowered coronary LPL. This was accompanied by limited cardiac lipid metabolite accumulation with an augmentation of cardiac insulin action. Our data for the first time links VEGFB to coronary LPL in regulation of cardiac metabolism. VEGFB may be cardioprotective in metabolic disorders like diabetes.
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Affiliation(s)
- Rui Shang
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Nathaniel Lal
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Chae Syng Lee
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Yajie Zhai
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Karanjit Puri
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Oscar Seira
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Robert C Boushel
- School of Kinesiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ibrahim Sultan
- Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
| | - Markus Räsänen
- Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
| | - Kari Alitalo
- Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
| | - Bahira Hussein
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Brian Rodrigues
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
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Ye X, Gaucher JF, Vidal M, Broussy S. A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics. Molecules 2021; 26:6759. [PMID: 34833851 PMCID: PMC8625919 DOI: 10.3390/molecules26226759] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 12/27/2022] Open
Abstract
The vascular endothelial growth factor (VEGF) family of cytokines plays a key role in vasculogenesis, angiogenesis, and lymphangiogenesis. VEGF-A is the main member of this family, alongside placental growth factor (PlGF), VEGF-B/C/D in mammals, and VEGF-E/F in other organisms. To study the activities of these growth factors under physiological and pathological conditions, resulting in therapeutic applications in cancer and age-related macular degeneration, blocking ligands have been developed. These have mostly been large biomolecules like antibodies. Ligands with high affinities, at least in the nanomolar range, and accurate structural data from X-ray crystallography and NMR spectroscopy have been described. They constitute the main focus of this overview, which evidences similarities and differences in their binding modes. For VEGF-A ligands, and to a limited extent also for PlGF, a transition is now observed towards developing smaller ligands like nanobodies and peptides. These include unnatural amino acids and chemical modifications for designed and improved properties, such as serum stability and greater affinity. However, this review also highlights the scarcity of such small molecular entities and the striking lack of small organic molecule ligands. It also shows the gap between the rather large array of ligands targeting VEGF-A and the general absence of ligands binding other VEGF members, besides some antibodies. Future developments in these directions are expected in the upcoming years, and the study of these growth factors and their promising therapeutic applications will be welcomed.
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Affiliation(s)
- Xiaoqing Ye
- Faculté de Pharmacie de Paris, Université de Paris, CiTCoM, 8038 CNRS, U 1268 INSERM, 75006 Paris, France; (X.Y.); (M.V.)
| | - Jean-François Gaucher
- Laboratoire de Cristallographie et RMN Biologiques, Faculté de Pharmacie de Paris, Université de Paris, CiTCoM, 8038 CNRS, 75006 Paris, France;
| | - Michel Vidal
- Faculté de Pharmacie de Paris, Université de Paris, CiTCoM, 8038 CNRS, U 1268 INSERM, 75006 Paris, France; (X.Y.); (M.V.)
- Service Biologie du Médicament, Toxicologie, AP-HP, Hôpital Cochin, 75014 Paris, France
| | - Sylvain Broussy
- Faculté de Pharmacie de Paris, Université de Paris, CiTCoM, 8038 CNRS, U 1268 INSERM, 75006 Paris, France; (X.Y.); (M.V.)
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Narayana S, Ahmed MG, Gowda BHJ, Shetty PK, Nasrine A, Thriveni M, Noushida N, Sanjana A. Recent advances in ocular drug delivery systems and targeting VEGF receptors for management of ocular angiogenesis: A comprehensive review. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2021. [DOI: 10.1186/s43094-021-00331-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Abstract
Background
Angiogenic ocular diseases address the main source of vision impairment or irreversible vision loss. The angiogenesis process depends on the balance between the pro-angiogenic and anti-angiogenic factors. An imbalance between these factors leads to pathological conditions in the body. The vascular endothelial growth factor is the main cause of pathological conditions in the ocular region. Intravitreal injections of anti-angiogenic drugs are selective, safe, specific and revolutionized treatment for ocular angiogenesis. But intravitreal injections are invasive techniques with other severe complications. The area of targeting vascular endothelial growth factor receptors progresses with novel approaches and therapeutically based hope for best clinical outcomes for patients through the developments in anti-angiogenic therapy.
Main text
The present review article gathers prior knowledge about the vascular endothelial growth factor and associated receptors with other angiogenic and anti-angiogenic factors involved in ocular angiogenesis. A focus on the brief mechanism of vascular endothelial growth factor inhibitors in the treatment of ocular angiogenesis is elaborated. The review also covers various recent novel approaches available for ocular drug delivery by comprising a substantial amount of research works. Besides this, we have also discussed in detail the adoption of nanotechnology-based drug delivery systems in ocular angiogenesis by comprising literature having recent advancements. The clinical applications of nanotechnology in terms of ocular drug delivery, risk analysis and future perspectives relating to the treatment approaches for ocular angiogenesis have also been presented.
Conclusion
The novel ocular drug delivery systems involving nanotechnologies are of great importance in the ophthalmological sector to overcome traditional treatments with many drawbacks. This article gives a detailed insight into the various approaches that are currently available to be a road map for future research in the field of ocular angiogenesis disease management.
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Abe I, Islam F, Lo CY, Liew V, Pillai S, Lam AK. VEGF-A/VEGF-B/VEGF-C expressions in non-hereditary, non-metastatic phaeochromocytoma. Histol Histopathol 2021; 36:645-652. [PMID: 33734425 DOI: 10.14670/hh-18-329] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Vascular endothelial growth factor (VEGF) is important in pathogenesis of different cancers. The aim of this study is to investigate the relationships between different VEGFs and clinicopathological factors in patients with phaeochromocytomas. Twenty patients (10 men; 10 women) with non-hereditary, non-metastatic phaeochromocytomas were examined for VEGF mRNA expressions by polymerase chain reaction. The expressions were correlated with the clinical and pathological factors of the patients. In addition, mouse double minute 2 (MDM2) expression in these tumours were studied by immunohistochemistry. High expressions of VEGF-A, VEGF-B, and VEGF-C mRNA were detected in 11 (55%), 9 (45%), and 9 (45%) of the tumours respectively. High expression of VEGF-A in phaeochromocytomas was significantly correlated with the tumour size (p=0.025) but did not correlate with patients' age, gender, and tumour laterality. Besides, there was a trend of VEGF-A expression correlated with MDM2 expression (p=0.064). On the other hand, expressions of VEGF-B and VEGF-C were not significantly correlated with tumour size, patients' age, gender, tumour laterality, and MDM2 expression. In addition, high expressions of VEGF-B and VEGF-A were associated with increase of tumour size (p=0.042). Co-expression of different VEGFs did not correlate with MDM2 expression. To conclude, there is a role for VEGF-A/VEGF-B/VEGF-C in the pathogenesis of non-hereditary, non-metastatic phaeochromocytomas.
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Affiliation(s)
- Ichiro Abe
- School of Medicine, Griffith University, Gold Coast, Queensland, Australia
- Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Chung Yau Lo
- Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
| | - Victor Liew
- Department of Surgery, Gold Coast Private Hospital, Gold Coast, Queensland, Australia
| | - Suja Pillai
- School of Medicine, Griffith University, Gold Coast, Queensland, Australia
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia
| | - Alfred K Lam
- School of Medicine, Griffith University, Gold Coast, Queensland, Australia
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia.
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Snake venom vascular endothelial growth factors (svVEGFs): Unravelling their molecular structure, functions, and research potential. Cytokine Growth Factor Rev 2021; 60:133-143. [PMID: 34090786 DOI: 10.1016/j.cytogfr.2021.05.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/18/2021] [Accepted: 05/24/2021] [Indexed: 02/07/2023]
Abstract
Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis, a physiological process characterized by the formation of new vessels from a preexisting endothelium. VEGF has also been implicated in pathologic states, such as neoplasias, intraocular neovascular disorders, among other conditions. VEGFs are distributed in seven different families: VEGF-A, B, C, D, and PIGF (placental growth factor), which are identified in mammals; VEGF-E, which are encountered in viruses; and VEGF-F or svVEGF (snake venom VEGF) described in snake venoms. This is the pioneer review of svVEGF family, exploring its distribution among the snake venoms, molecular structure, main functions, and potential applications.
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Vascular Endothelial Growth Factor Biology and Its Potential as a Therapeutic Target in Rheumatic Diseases. Int J Mol Sci 2021; 22:ijms22105387. [PMID: 34065409 PMCID: PMC8161097 DOI: 10.3390/ijms22105387] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/14/2021] [Accepted: 05/18/2021] [Indexed: 12/11/2022] Open
Abstract
Rheumatic diseases constitute a diversified group of diseases distinguished by arthritis and often involve other organs. The affected individual has low quality of life, productivity even life-threatening in some severe conditions. Moreover, they impose significant economic and social burdens. In recent years, the patient outcome has been improved significantly due to clearer comprehension of the pathology of rheumatic diseases and the effectiveness of "treat to target" therapies. However, the high cost and the adverse effects are the concerns and full remissions are not often observed. One of the main processes that contributes to the pathogenesis of rheumatic diseases is angiogenesis. Vascular endothelial growth factor (VEGF), a central mediator that regulates angiogenesis, has different isoforms and functions in various physiological processes. Increasing evidence suggests an association between the VEGF system and rheumatic diseases. Anti-VEGF and VEGF receptor (VEGFR) therapies have been used to treat several cancers and eye diseases. This review summarizes the current understanding of VEGF biology and its role in the context of rheumatic diseases, the contribution of VEGF bioavailability in the pathogenesis of rheumatic diseases, and the potential implications of therapeutic approaches targeting VEGF for these diseases.
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Lin H, Yang Y, Hou C, Zheng J, Lv G, Mao R, Xu P, Chen S, Zhou Y, Wang P, Zhou D. Identification of COL6A1 as the Key Gene Associated with Antivascular Endothelial Growth Factor Therapy in Glioblastoma Multiforme. Genet Test Mol Biomarkers 2021; 25:334-345. [PMID: 33970702 DOI: 10.1089/gtmb.2020.0279] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Background: Vascular endothelial growth factors (VEGFs) are important for glioblastoma multiforme (GBM) growth and development. However, the effects of VEGF-targeting drugs in primary GBM remain poorly understood. Aim: We aimed to explore the key genes correlated with VEGF expression and prognosis and elucidate their potential implications in GBM anti-VEGF therapy. Materials and Methods: RNA-seq data with the corresponding clinicopathological information was retrieved from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas. Weighted gene coexpression network analyses was performed on differentially expressed genes to construct coexpression modules and investigate their correlation with VEGFs. Functional enrichment analyses were performed based on the coexpressed genes from the most promising modules. CytoHubba and Kaplan-Meier analyses were implemented to identify the key genes in the modules of interest. The oncomine database, quantitative reverse transcription PCR, and the Human Protein Atlas were used to investigate the expression characteristics of the identified key genes. Results: Four modules (cyan, green, purple, and tan) correlated significantly with VEGF expression. Enrichment analyses suggested that extracellular matrix-receptor interaction, growth factor binding, and the PI3K-Akt pathways were involved in VEGF expression. Four hub genes (COL6A1, SNRPG, COL3A1, and AHI1) associated with VEGF were identified. Among them, COL6A1 was regarded as the key gene associated with anti-VEGF therapy. Further, COL6A1 was upregulated in GBM compared to that in normal brain tissues. COL6A1 overexpression was associated with a poor prognosis. Conclusion: COL6A1 was identified as the key gene associated with anti-VEGF therapy and may provide novel insight into GBM targeted therapy.
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Affiliation(s)
- Han Lin
- Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shantou University Medical College, Shantou, Guangdong, China
| | - Yong Yang
- Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Chongxian Hou
- Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jiantao Zheng
- Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Guangzhao Lv
- Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shantou University Medical College, Shantou, Guangdong, China
| | - Rui Mao
- Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Peihong Xu
- Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shantou University Medical College, Shantou, Guangdong, China
| | - Shanwei Chen
- Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shantou University Medical College, Shantou, Guangdong, China
| | - Yujun Zhou
- Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Southern Medical University, Guangzhou, China
| | - Peng Wang
- Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Dong Zhou
- Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Jia JD, Jiang WG, Luo X, Li RR, Zhao YC, Tian G, Li YN. Vascular endothelial growth factor B inhibits insulin secretion in MIN6 cells and reduces Ca 2+ and cyclic adenosine monophosphate levels through PI3K/AKT pathway. World J Diabetes 2021; 12:480-498. [PMID: 33889292 PMCID: PMC8040075 DOI: 10.4239/wjd.v12.i4.480] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/25/2021] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Type 2 diabetes (T2D) is characterized by insufficient insulin secretion caused by defective pancreatic β-cell function or insulin resistance, resulting in an increase in blood glucose. However, the mechanism involved in this lack of insulin secretion is unclear. The level of vascular endothelial growth factor B (VEGF-B) is significantly increased in T2D patients. The inactivation of VEGF-B could restore insulin sensitivity in db/db mice by reducing fatty acid accumulation. It is speculated that VEGF-B is related to pancreatic β-cell dysfunction and is an important factor affecting β-cell secretion of insulin. As an in vitro model of normal pancreatic β-cells, the MIN6 cell line can be used to analyze the mechanism of insulin secretion and related biological effects.
AIM To study the role of VEGF-B in the insulin secretion signaling pathway in MIN6 cells and explore the effect of VEGF-B on blood glucose regulation.
METHODS The MIN6 mouse pancreatic islet β-cell line was used as the model system. By administering exogenous VEGF-B protein or knocking down VEGF-B expression in MIN6 cells, we examined the effects of VEGF-B on insulin secretion, Ca2+ and cyclic adenosine monophosphate (cAMP) levels, and the insulin secretion signaling pathway.
RESULTS Exogenous VEGF-B inhibited the secretion of insulin and simultaneously reduced the levels of Ca2+ and cAMP in MIN6 cells. Exogenous VEGF-B also reduced the expression of phospholipase C gamma 1 (PLCγ1), phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (AKT), and other proteins in the insulin secretion pathway. Upon knockdown of VEGF-B, MIN6 cells exhibited increased insulin secretion and Ca2+ and cAMP levels and upregulated expression of PLCγ1, PI3K, AKT, and other proteins.
CONCLUSION VEGF-B can regulate insulin secretion by modulating the levels of Ca2+ and cAMP. VEGF-B involvement in insulin secretion is related to the expression of PLCγ1, PI3K, AKT, and other signaling proteins. These results provide theoretical support and an experimental basis for the study of VEGF-B in the pathogenesis of T2D.
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Affiliation(s)
- Jing-Dan Jia
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Wen-Guo Jiang
- Department of Pharmacy, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Xu Luo
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Rong-Rong Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Yu-Chi Zhao
- Department of Surgery, Yantaishan Hospital, Yantai 264001, Shandong Province, China
| | - Geng Tian
- Department of Pharmacy, Binzhou Medical University, Yantai 264003, Shandong Province, China
| | - Ya-Na Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264003, Shandong Province, China
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Ma Y, Wang W, Liu L, Liu Y, Bi W. Co-expression of VEGF-B and FLT-1 correlates with malignancy and prognosis of gastric cancer. Biomark Med 2021; 15:481-488. [PMID: 33856262 DOI: 10.2217/bmm-2020-0608] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Background: This study aims to investigate the correlation of VEGF-B and FLT-1 co-expression with the prognosis of gastric cancer (GC). Materials & methods: Primary GC samples and adjacent tissues were obtained from 96 patients. Results: Both VEGF-B and FLT-1 were testified to be upregulated in the human GC compared with adjacent tissues. Spearman's rank correlation analysis indicated that VEGF-B and FLT-1 expression were correlated (r = 0.321, p = 0.0015). High VEGF-B and FLT-1 co-expression patients showed poor prognosis when compared with low VEGF-B and FLT-1 co-expression patients (p = 0.0169). Conclusion: The high co-expression of VEGF-B and FLT-1 in GC shows a poor prognosis of overall survival, and targeted therapy against the interaction between VEGF-B and FLT-1 is worth further detailed analysis.
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Affiliation(s)
- Yanpeng Ma
- Department of General Surgery of East District, Second Hospital of Hebei Medical University, no. 215 Heping East Road, Xinhua District, Shijiazhuang, 050000, Hebei, China
| | - Wenyao Wang
- Department of General Surgery of East District, Second Hospital of Hebei Medical University, no. 215 Heping East Road, Xinhua District, Shijiazhuang, 050000, Hebei, China
| | - Longlong Liu
- Department of General Surgery of East District, Second Hospital of Hebei Medical University, no. 215 Heping East Road, Xinhua District, Shijiazhuang, 050000, Hebei, China
| | - Yang Liu
- Department of Vascular Surgery, Second Hospital of Hebei Medical University, no. 215 Heping East Road, Xinhua District, Shijiazhuang, 050000, Hebei, China
| | - Wei Bi
- Department of Vascular Surgery, Second Hospital of Hebei Medical University, no. 215 Heping East Road, Xinhua District, Shijiazhuang, 050000, Hebei, China
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42
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Llorián-Salvador M, Barabas P, Byrne EM, Lechner J, Augustine J, Curtis TM, Chen M, Xu H. VEGF-B Is an Autocrine Gliotrophic Factor for Müller Cells under Pathologic Conditions. Invest Ophthalmol Vis Sci 2021; 61:35. [PMID: 32945843 PMCID: PMC7509798 DOI: 10.1167/iovs.61.11.35] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose Müller glia are important in retinal health and disease and are a major source of retinal VEGF-A. Of the different VEGF family members, the role of VEGF-A in retinal health and disease has been studied extensively. The potential contribution of other VEGF family members to retinal pathophysiology, however, remains poorly defined. This study aimed to understand the role of VEGF-B in Müller cell pathophysiology. Methods The expression of different VEGFs and their receptors in human MIO-M1 and mouse QMMuC-1 Müller cell lines and primary murine Müller cells was examined by RT-PCR, ELISA, and Western blot. The effect of recombinant VEGF-B or VEGF-B neutralization on Müller cell viability and survival under normal, hypoxic, and oxidative (4-hydroxynonenal [4-HNE]) conditions was evaluated by Alamar Blue, Yo-Pro uptake, and immunocytochemistry. The expression of glial fibrillary acidic protein, aquaporin-4, inward rectifying K+ channel subtype 4.1, glutamine synthetase, and transient receptor potential vanilloid 4 under different treatment conditions was examined by RT-PCR, immunocytochemistry, and Western blot. Transient receptor potential vanilloid 4 channel activity was assessed using a Fura-2–based calcium assay. Results VEGF-B was expressed in Müller cells at the highest levels compared with other members of the VEGF family. VEGF-B neutralization did not affect Müller cell viability or functionality under normal conditions, but enhanced hypoxia– or 4-HNE–induced Müller cell death and decreased inward rectifying K+ channel subtype 4.1 and aquaporin-4 expression. Recombinant VEGF-B restored Müller cell glutamine synthetase expression under hypoxic conditions and protected Müller cells from 4-HNE–induced damage by normalizing transient receptor potential vanilloid 4 channel expression and activity. Conclusions Autocrine production of VEGF-B protects Müller cells under pathologic conditions.
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Affiliation(s)
- María Llorián-Salvador
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Peter Barabas
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Eimear M Byrne
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Judith Lechner
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Josy Augustine
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Timothy M Curtis
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Mei Chen
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
| | - Heping Xu
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT9 7BL. Belfast, United Kingdom
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Neuroprotective Effect of Vascular Endothelial Growth Factor on Motoneurons of the Oculomotor System. Int J Mol Sci 2021; 22:ijms22020814. [PMID: 33467517 PMCID: PMC7830098 DOI: 10.3390/ijms22020814] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/11/2021] [Accepted: 01/13/2021] [Indexed: 01/04/2023] Open
Abstract
Vascular endothelial growth factor (VEGF) was initially characterized as a potent angiogenic factor based on its activity on the vascular system. However, it is now well established that VEGF also plays a crucial role as a neuroprotective factor in the nervous system. A deficit of VEGF has been related to motoneuronal degeneration, such as that occurring in amyotrophic lateral sclerosis (ALS). Strikingly, motoneurons of the oculomotor system show lesser vulnerability to neurodegeneration in ALS compared to other motoneurons. These motoneurons presented higher amounts of VEGF and its receptor Flk-1 than other brainstem pools. That higher VEGF level could be due to an enhanced retrograde input from their target muscles, but it can also be produced by the motoneurons themselves and act in an autocrine way. By contrast, VEGF’s paracrine supply from the vicinity cells, such as glial cells, seems to represent a minor source of VEGF for brainstem motoneurons. In addition, ocular motoneurons experiment an increase in VEGF and Flk-1 level in response to axotomy, not observed in facial or hypoglossal motoneurons. Therefore, in this review, we summarize the differences in VEGF availability that could contribute to the higher resistance of extraocular motoneurons to injury and neurodegenerative diseases.
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Zhang J, Liu X, Ma K, Chen M, Xu H, Niu X, Gu H, Wang R, Chen X, Sun H. Collagen/heparin scaffold combined with vascular endothelial growth factor promotes the repair of neurological function in rats with traumatic brain injury. Biomater Sci 2021; 9:745-764. [DOI: 10.1039/c9bm01446b] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The objective of this study was to evaluate the therapy effects of a novel biological scaffold containing heparin, collagen and vascular endothelial growth factor (VEGF) in treating traumatic brain injury (TBI).
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Affiliation(s)
- Jian Zhang
- Tianjin Key Laboratory of Neurotrauma Repair
- Institute of Traumatic Brain Injury and Neuroscience
- Characteristic Medical Center of Chinese People's Armed Police Force
- Tianjin 300162
- China
| | - Xiaoyin Liu
- Tianjin Key Laboratory of Neurotrauma Repair
- Institute of Traumatic Brain Injury and Neuroscience
- Characteristic Medical Center of Chinese People's Armed Police Force
- Tianjin 300162
- China
| | - Ke Ma
- Tianjin Key Laboratory of Neurotrauma Repair
- Institute of Traumatic Brain Injury and Neuroscience
- Characteristic Medical Center of Chinese People's Armed Police Force
- Tianjin 300162
- China
| | - Miao Chen
- Affiliated Hospital of Traditional Chinese Medicine
- Xinjiang Medical University
- Urumqi
- China
| | - Huiyou Xu
- Tianjin Key Laboratory of Neurotrauma Repair
- Institute of Traumatic Brain Injury and Neuroscience
- Characteristic Medical Center of Chinese People's Armed Police Force
- Tianjin 300162
- China
| | | | - Haoran Gu
- The 947th hospital of Chinese People's Liberation Army
- Xinjiang
- China
| | - Renjie Wang
- Tianjin Key Laboratory of Neurotrauma Repair
- Institute of Traumatic Brain Injury and Neuroscience
- Characteristic Medical Center of Chinese People's Armed Police Force
- Tianjin 300162
- China
| | - Xuyi Chen
- Tianjin Key Laboratory of Neurotrauma Repair
- Institute of Traumatic Brain Injury and Neuroscience
- Characteristic Medical Center of Chinese People's Armed Police Force
- Tianjin 300162
- China
| | - HongTao Sun
- Tianjin Key Laboratory of Neurotrauma Repair
- Institute of Traumatic Brain Injury and Neuroscience
- Characteristic Medical Center of Chinese People's Armed Police Force
- Tianjin 300162
- China
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Riccardi C, Napolitano E, Platella C, Musumeci D, Melone MAB, Montesarchio D. Anti-VEGF DNA-based aptamers in cancer therapeutics and diagnostics. Med Res Rev 2020; 41:464-506. [PMID: 33038031 DOI: 10.1002/med.21737] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 09/12/2020] [Accepted: 09/23/2020] [Indexed: 12/13/2022]
Abstract
The vascular endothelial growth factor (VEGF) family and its receptors play fundamental roles not only in physiological but also in pathological angiogenesis, characteristic of cancer progression. Aiming at finding putative treatments for several malignancies, various small molecules, antibodies, or protein-based drugs have been evaluated in vitro and in vivo as VEGF inhibitors, providing efficient agents approved for clinical use. Due to the high clinical importance of VEGF, also a great number of anti-VEGF nucleic acid-based aptamers-that is, oligonucleotides able to bind with high affinity and specificity a selected biological target-have been developed as promising agents in anticancer strategies. Notable research efforts have been made in optimization processes of the identified aptamers, searching for increased target affinity and/or bioactivity by exploring structural analogues of the lead compounds. This review is focused on recent studies devoted to the development of DNA-based aptamers designed to target VEGF. Their therapeutic potential as well as their significance in the construction of highly selective biosensors is here discussed.
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Affiliation(s)
- Claudia Riccardi
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy.,Department of Advanced Medical and Surgical Sciences, 2nd Division of Neurology, Center for Rare Diseases and Inter-University Center for Research in Neurosciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Ettore Napolitano
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy
| | - Chiara Platella
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy
| | - Domenica Musumeci
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy.,Institute of Biostructures and Bioimages, Naples, Italy
| | - Mariarosa A B Melone
- Department of Advanced Medical and Surgical Sciences, 2nd Division of Neurology, Center for Rare Diseases and Inter-University Center for Research in Neurosciences, University of Campania Luigi Vanvitelli, Naples, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Daniela Montesarchio
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy
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Assareh E, Mehrnejad F, Asghari SM. Structural Studies on an Anti-Angiogenic Peptide Using Molecular Modeling. IRANIAN JOURNAL OF BIOTECHNOLOGY 2020; 18:e2553. [PMID: 34056022 PMCID: PMC8148638 DOI: 10.30498/ijb.2020.2553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Development of VEGF antagonists, which inhibit its interaction with the receptors, is a widely used strategy for the inhibition of angiogenesis and tumor growth. OBJECTIVES In the present study, a VEGFR-1 antagonistic peptide was designed and its potential for binding to VEGFR-1 and VEGFR-2 was evaluated by theoretical studies. MATERIALS AND METHODS Based on the X-ray structure of VEGF-B/VEGFR-1 D2 (PDB ID: 2XAC), an antagonistic peptide (known as VGB1) was designed, and its model structure was constructed using homology modeling in the MODELLER, version 9.16. The validity of the modeled structures was estimated employing several web tools. Finally, one model was chosen and molecular dynamics (MD) simulation was applied using the GROMACS package, version 5.1.4, to allow conformational relaxation of the structure. Next, docking process of the peptide with VEGFR-1 and VEGFR-2 was performed by HADDOCK web server and the docking structures were optimized by MD simulation for 20 ns. The far-UV circular dichroism (CD) spectrum of VGB1 was recorded to evaluate the overall structure of the peptide. RESULTS The far-UV CD spectrum indicated that VGB1 contains α helix structure. The results from docking studies suggested that Van der Waals and nonpolar interactions play the most important role in the peptide binding to VEGFR-1. In addition, our results implicated the relevance of both Van der Waals and electrostatic interactions in the formation of complex between VGB1 and VEGFR-2. In addition to the common binding residues in the corresponding region of VEGF-A and VEGF-B, additional binding residues also were predicted for the interaction of VGB1 with VEGFR-1 and VEGFR-2. CONCLUSIONS The results of MD and molecular docking simulations predicted that VGB1 recognizes both VEGFR-1 and VEGFR-2, which may lead to the prevention of the downstream signaling triggered by these receptors.
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Affiliation(s)
- Elham Assareh
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Faramarz Mehrnejad
- Department of Life Sciences Engineering, Faculty of New Sciences & Technology, University of Tehran, Tehran, Iran
| | - S Mohsen Asghari
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
- Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
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Affiliation(s)
- Mauro Giacca
- King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences and Medicine, London, UK; University of Trieste, Department of Medical, Surgical and Health Sciences, Trieste, Italy.
| | - Fabio A Recchia
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy; Fondazione G. Monasterio, Pisa, Italy; Cardiovascular Research Institute, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
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Hemanthakumar KA, Kivelä R. Angiogenesis and angiocrines regulating heart growth. VASCULAR BIOLOGY 2020; 2:R93-R104. [PMID: 32935078 PMCID: PMC7487598 DOI: 10.1530/vb-20-0006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 06/22/2020] [Indexed: 12/17/2022]
Abstract
Endothelial cells (ECs) line the inner surface of all blood and lymphatic vessels throughout the body, making endothelium one of the largest tissues. In addition to its transport function, endothelium is now appreciated as a dynamic organ actively participating in angiogenesis, permeability and vascular tone regulation, as well as in the development and regeneration of tissues. The identification of endothelial-derived secreted factors, angiocrines, has revealed non-angiogenic mechanisms of endothelial cells in both physiological and pathological tissue remodeling. In the heart, ECs play a variety of important roles during cardiac development as well as in growth, homeostasis and regeneration of the adult heart. To date, several angiocrines affecting cardiomyocyte growth in response to physiological or pathological stimuli have been identified. In this review, we discuss the effects of angiogenesis and EC-mediated signaling in the regulation of cardiac hypertrophy. Identification of the molecular and metabolic signals from ECs during physiological and pathological cardiac growth could provide novel therapeutic targets to treat heart failure, as endothelium is emerging as one of the potential target organs in cardiovascular and metabolic diseases.
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Affiliation(s)
- Karthik Amudhala Hemanthakumar
- Stem cells and Metabolism Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Wihuri Research Institute, Helsinki, Finland
| | - Riikka Kivelä
- Stem cells and Metabolism Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Wihuri Research Institute, Helsinki, Finland
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Mtshali Z, Moodley J, Naicker T. An Insight into the Angiogenic and Lymphatic Interplay in Pre-eclampsia Comorbid with HIV Infection. Curr Hypertens Rep 2020; 22:35. [PMID: 32200445 DOI: 10.1007/s11906-020-01040-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW To provide insight on the imbalance of angiogenic and lymphangiogenic factors in pre-eclampsia, as well as highlight polymorphism in genes related to angiogenesis and lymphangiogenesis. RECENT FINDINGS The pregnancy-specific disorder pre-eclampsia is diagnosed by the presence of hypertension with/without proteinuria, after 20 weeks of gestation. The pathogenesis of pre-eclampsia remains ambiguous, but research over the years has identified an imbalance in maternal and foetal factors. Familial predisposition and gene variation are also linked to pre-eclampsia development. The sFlt-1/PIGF ratio has attracted great attention over the years; more recently several researchers have reported that a sFlt-1/PIGF ratio of ≤ 38 can be used to predict short-term absence of pre-eclampsia. This ratio has the potential to prevent adverse pregnancy outcomes and reduce healthcare costs significantly. Genome-wide studies have additionally identified variation in the foetal gene near Flt-1. The development of preeclampsia is not limited to the maternal interface, but foetal involvement as well as genetic interplay is associated with the disorder.
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Affiliation(s)
- Zamahlabangane Mtshali
- Optics and Imaging Centre, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
| | - Jagidesa Moodley
- Department of Obstetrics and Gynaecology and Women's Health and HIV Research Group, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - Thajasvarie Naicker
- Optics and Imaging Centre, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa
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Zhu X, Wang Y, Zhu L, Zhu Y, Zhang K, Wang L, Bai H, Yang Q, Ben J, Zhang H, Li X, Xu Y, Chen Q. Class A1 scavenger receptor prevents obesity-associated blood pressure elevation through suppressing overproduction of vascular endothelial growth factor B in macrophages. Cardiovasc Res 2020; 117:547-560. [PMID: 32044963 DOI: 10.1093/cvr/cvaa030] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 11/17/2019] [Accepted: 01/31/2020] [Indexed: 12/14/2022] Open
Abstract
AIMS Dysfunctional innate immune function and inflammation contributes to the pathogenesis of obesity-associated hypertension, in which macrophage infiltration in the perivascular adipose tissue (PVAT) plays a key role. However, the mechanisms behind it are not well understood. Class A1 scavenger receptor (SR-A1) is one of the major pattern recognition receptors in modulating macrophage activity, and here, we aimed to investigate its role in obesity-associated hypertension. METHODS AND RESULTS Both diet-induced and genetic obesity were generated in mice. Deficiency in SR-A1 aggravated the obesity-induced blood pressure (BP) elevation and endothelial dysfunction in mice. The BP-elevating effect of SR-A1 deficiency was blocked by the down-regulation of vascular endothelial growth factor B (VEGF-B) in obese mice. Overexpression of VEGF-B raised BP in the obese mice but not in normal mice. Administration of fucoidan, a ligand of SR-A1, lowered BP, and VEGF-B levels in Sr-a1+/+ but not in Sr-a1-/- obese mice. CONCLUSION These results reveal a new link between PVAT and vascular biology in obesity orchestrated by the SR-A1/VEGF-B axis in macrophages. SR-A1 and VEGF-B may be promising therapeutic targets in the treatment of obesity-associated hypertension.
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Affiliation(s)
- Xudong Zhu
- Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Liongmian Road, Jiangning District, Nanjing 211166, China
| | - Yan Wang
- Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Liongmian Road, Jiangning District, Nanjing 211166, China
| | - Liu Zhu
- Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Liongmian Road, Jiangning District, Nanjing 211166, China.,Cardiovascular Medicine Department, The Second Affiliated Hospital of Soochow University, Sanxiang Road, Gusu District, Suzhou 215004, China
| | - Ye Zhu
- Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Liongmian Road, Jiangning District, Nanjing 211166, China
| | - Kun Zhang
- Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Liongmian Road, Jiangning District, Nanjing 211166, China
| | - Lei Wang
- Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Liongmian Road, Jiangning District, Nanjing 211166, China
| | - Hui Bai
- Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Liongmian Road, Jiangning District, Nanjing 211166, China
| | - Qing Yang
- Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Liongmian Road, Jiangning District, Nanjing 211166, China
| | - Jingjing Ben
- Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Liongmian Road, Jiangning District, Nanjing 211166, China
| | - Hanwen Zhang
- Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Liongmian Road, Jiangning District, Nanjing 211166, China
| | - Xiaoyu Li
- Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Liongmian Road, Jiangning District, Nanjing 211166, China
| | - Yong Xu
- Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Liongmian Road, Jiangning District, Nanjing 211166, China
| | - Qi Chen
- Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Liongmian Road, Jiangning District, Nanjing 211166, China
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