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Brown SN, Shallie P, Sierra CA, Nayak N, Odibo AO, Monaghan-Nichols P, Nayak NR. Spatiotemporal Angiogenic Patterns in the Development of the Mouse Fetal Blood-Brain Barrier System During Pregnancy. Int J Mol Sci 2025; 26:3862. [PMID: 40332505 PMCID: PMC12027533 DOI: 10.3390/ijms26083862] [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: 02/13/2025] [Revised: 04/07/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025] Open
Abstract
Understanding the timing of fetal brain vulnerability to inflammatory changes in pregnancy complications is crucial for predicting neurodevelopmental risks. Beyond the placenta, the developing brain's vascular system is believed to form a secondary defense, the blood-brain barrier (BBB), which restricts harmful substances that could disrupt neurodevelopment. However, the precise timing and mechanisms underlying BBB development are poorly understood. In this study, we examined the spatiotemporal expression of key BBB components and fetal brain vascularization in mice from gestational days (GD) 10 to 18. Fetal brain sections were immunostained to identify BBB components, including CD31, Factor VIII, NG2, and claudin-5. Our results showed that endothelial precursor cells form the primitive vascular network in a caudal-to-rostral gradient by GD10, with pericyte recruitment stabilizing vessels by GD12 in a lateral-to-medial gradient that aligns with neurogenesis, despite some regional exceptions. However, Factor VIII was not detected until GD15, and claudin-5 until GD18, suggesting a significant delay in endothelial maturation and tight junction formation. These findings highlight the critical timing of structural developments in the fetal brain vasculature and its vulnerability to placental diseases, laying the groundwork for future research on the impact of placental disorders on fetal brain development and potential therapeutic interventions.
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Affiliation(s)
- Samuel Nofsinger Brown
- Department of Obstetrics and Gynecology, University of Missouri Kansas City School of Medicine, Kansas, MO 64108, USA; (S.N.B.); (P.S.); (N.N.); (A.O.O.)
- University of Missouri School of Medicine, Columbia, MO 65212, USA;
| | - Philemon Shallie
- Department of Obstetrics and Gynecology, University of Missouri Kansas City School of Medicine, Kansas, MO 64108, USA; (S.N.B.); (P.S.); (N.N.); (A.O.O.)
| | - Connor A. Sierra
- University of Missouri School of Medicine, Columbia, MO 65212, USA;
| | - Neha Nayak
- Department of Obstetrics and Gynecology, University of Missouri Kansas City School of Medicine, Kansas, MO 64108, USA; (S.N.B.); (P.S.); (N.N.); (A.O.O.)
| | - Anthony O. Odibo
- Department of Obstetrics and Gynecology, University of Missouri Kansas City School of Medicine, Kansas, MO 64108, USA; (S.N.B.); (P.S.); (N.N.); (A.O.O.)
| | - Paula Monaghan-Nichols
- Department of Biomedical Sciences, University of Missouri Kansas City School of Medicine, Kansas, MO 64108, USA;
| | - Nihar R. Nayak
- Department of Obstetrics and Gynecology, University of Missouri Kansas City School of Medicine, Kansas, MO 64108, USA; (S.N.B.); (P.S.); (N.N.); (A.O.O.)
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Liu K, Kang Z, Yang M, Chen F, Xia M, Dai W, Zheng S, Chen H, Lu QR, Zhou W, Lin Y. The role of oligodendrocyte progenitor cells in the spatiotemporal vascularization of the human and mouse neocortex. Glia 2025; 73:140-158. [PMID: 39392208 DOI: 10.1002/glia.24625] [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: 01/09/2024] [Revised: 08/21/2024] [Accepted: 09/27/2024] [Indexed: 10/12/2024]
Abstract
Brain vasculature formation begins with vessel invasion from the perineural vascular plexus, which expands through vessel sprouting and growth. Recent studies have indicated the existence of oligodendrocyte-vascular crosstalk during development. However, the relationship between oligodendrocyte progenitor cells (OPCs) and the ordered spatiotemporal vascularization of the neocortex has not been elucidated. Our findings suggest that OPCs play a complex role in the vessel density of the embryonic and postnatal neocortex. Analyses of normal human and mouse embryonic cerebral cortex show that vascularization and OPC distribution are tightly controlled in a spatially and temporally restricted manner, exhibiting a positive correlation. Loss of OPCs at both embryonic and postnatal stages led to a reduction in vascular density, suggesting that OPC populations play a role in vascular density. Nonetheless, dynamic observation on cultured brain slices and staining of tissue sections indicate that OPC migration is unassociated with the proximity to blood vessels, primarily occurring along radial glial cell processes. Additionally, in vitro experiments demonstrate that OPC secretions promote vascular endothelial cell (VEC) growth. Together, these observations suggest that vessel density is influenced by OPC secretions.
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Affiliation(s)
- Kaiyi Liu
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Zhiruo Kang
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China
| | - Min Yang
- Department of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Fangbing Chen
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China
| | - Mingyang Xia
- Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China
| | - Wenjuan Dai
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China
| | - Shiyi Zheng
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China
| | - Huiyao Chen
- Center for Molecular Medicine, Children's Hospital of Fudan University, Shanghai, China
| | - Q Richard Lu
- Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Wenhao Zhou
- Key Laboratory of Birth Defects, Children's Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Yifeng Lin
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China
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Boutom SM, Silva TP, Palecek SP, Shusta EV, Fernandes TG, Ashton RS. Central nervous system vascularization in human embryos and neural organoids. Cell Rep 2024; 43:115068. [PMID: 39693224 PMCID: PMC11975460 DOI: 10.1016/j.celrep.2024.115068] [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: 05/07/2024] [Revised: 09/25/2024] [Accepted: 11/22/2024] [Indexed: 12/20/2024] Open
Abstract
In recent years, neural organoids derived from human pluripotent stem cells (hPSCs) have offered a transformative pre-clinical platform for understanding central nervous system (CNS) development, disease, drug effects, and toxicology. CNS vasculature plays an important role in all these scenarios; however, most published studies describe CNS organoids that lack a functional vasculature or demonstrate rudimentary incorporation of endothelial cells or blood vessel networks. Here, we review the existing knowledge of vascularization during the development of different CNS regions, including the brain, spinal cord, and retina, and compare it to vascularized CNS organoid models. We highlight several areas of contrast where further bioengineering innovation is needed and discuss potential applications of vascularized neural organoids in modeling human CNS development, physiology, and disease.
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Affiliation(s)
- Sarah M Boutom
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
| | - Teresa P Silva
- Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal; Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Sean P Palecek
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, USA
| | - Eric V Shusta
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, USA; Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Tiago G Fernandes
- Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal; Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
| | - Randolph S Ashton
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA.
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Huang W, Liu Z, Li Z, Meng S, Huang Y, Gao M, Zhong N, Zeng S, Wang L, Zhao W. Identification of Immune Infiltration and Iron Metabolism-Related Subgroups in Autism Spectrum Disorder. J Mol Neurosci 2024; 74:12. [PMID: 38236354 DOI: 10.1007/s12031-023-02179-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 11/01/2023] [Indexed: 01/19/2024]
Abstract
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with a broad spectrum of symptoms and prognoses. Effective therapy requires understanding this variability. ASD children's cognitive and immunological development may depend on iron homoeostasis. This study employs a machine learning model that focuses on iron metabolism hub genes to identify ASD subgroups and describe immune infiltration patterns. A total of 97 control and 148 ASD samples were obtained from the GEO database. Differentially expressed genes (DEGs) and an iron metabolism gene collection achieved the intersection of 25 genes. Unsupervised cluster analysis determined molecular subgroups in individuals with ASD based on 25 genes related to iron metabolism. We assessed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, gene set variation analysis (GSVA), and immune infiltration analysis to compare iron metabolism subtype effects. We employed machine learning to identify subtype-predicting hub genes and utilized both training and validation sets to assess gene subtype prediction accuracy. ASD can be classified into two iron-metabolizing molecular clusters. Metabolic enrichment pathways differed between clusters. Immune infiltration showed that clusters differed immunologically. Cluster 2 had better immunological scores and more immune cells, indicating a stronger immune response. Machine learning screening identified SELENBP1 and CAND1 as important genes in ASD's iron metabolism signaling pathway. These genes express in the brain and have AUC values over 0.8, implying significant predictive power. The present study introduces iron metabolism signaling pathway indicators to predict ASD subtypes. ASD is linked to immune cell infiltration and iron metabolism disorders.
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Affiliation(s)
- Wenyan Huang
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510080, Guangdong, China
- Department of Pedodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, 510182, Guangdong, China
| | - Zhenni Liu
- Department of Pedodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, 510182, Guangdong, China
| | - Ziling Li
- Department of Pedodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, 510182, Guangdong, China
| | - Si Meng
- Department of Pedodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, 510182, Guangdong, China
| | - Yuhang Huang
- Department of Pedodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, 510182, Guangdong, China
| | - Min Gao
- Department of Pedodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, 510182, Guangdong, China
| | - Ning Zhong
- Department of Pedodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, 510182, Guangdong, China
| | - Sujuan Zeng
- Department of Pedodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, 510182, Guangdong, China
| | - Lijing Wang
- Department of Pedodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, 510182, Guangdong, China
| | - Wanghong Zhao
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510080, Guangdong, China.
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5
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Li M, Gao L, Zhao L, Zou T, Xu H. Toward the next generation of vascularized human neural organoids. Med Res Rev 2023; 43:31-54. [PMID: 35993813 DOI: 10.1002/med.21922] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 02/22/2022] [Accepted: 08/09/2022] [Indexed: 02/04/2023]
Abstract
Thanks to progress in the development of three-dimensional (3D) culture technologies, human central nervous system (CNS) development and diseases have been gradually deciphered by using organoids derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs). Selforganized neural organoids (NOs) have been used to mimic morphogenesis and functions of specific organs in vitro. Many NOs have been reproduced in vitro, such as those mimicking the human brain, retina, and spinal cord. However, NOs fail to capitulate to the maturation and complexity of in vivo neural tissues. The persistent issues with current NO cultivation protocols are inadequate oxygen supply and nutrient diffusion due to the absence of vascular networks. In vivo, the developing CNS is interpenetrated by vasculature that not only supplies oxygen and nutrients but also provides a structural template for neuronal growth. To address these deficiencies, recent studies have begun to couple NO culture with bioengineering techniques and methodologies, including genetic engineering, coculture, multidifferentiation, microfluidics and 3D bioprinting, and transplantation, which might promote NO maturation and create more functional NOs. These cutting-edge methods could generate an ever more reliable NO model in vitro for deciphering the codes of human CNS development, disease progression, and translational application. In this review, we will summarize recent technological advances in culture strategies to generate vascularized NOs (vNOs), with a special focus on cerebral- and retinal-organoid models.
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Affiliation(s)
- Minghui Li
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Lixiong Gao
- Department of Ophthalmology, Third Medical Center of PLA General Hospital, Beijing, China
| | - Ling Zhao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Ting Zou
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Haiwei Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
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6
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Cioffi S, Flore G, Martucciello S, Bilio M, Turturo MG, Illingworth E. VEGFR3 modulates brain microvessel branching in a mouse model of 22q11.2 deletion syndrome. Life Sci Alliance 2022; 5:5/12/e202101308. [PMID: 36216515 PMCID: PMC9553901 DOI: 10.26508/lsa.202101308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 09/23/2022] [Accepted: 09/23/2022] [Indexed: 11/24/2022] Open
Abstract
The loss of a single copy of TBX1 accounts for most of the clinical signs and symptoms of 22q11.2 deletion syndrome, a common genetic disorder that is characterized by multiple congenital anomalies and brain-related clinical problems, some of which likely have vascular origins. Tbx1 mutant mice have brain vascular anomalies, thus making them a useful model to gain insights into the human disease. Here, we found that the main morphogenetic function of TBX1 in the mouse brain is to suppress vessel branching morphogenesis through regulation of Vegfr3 We demonstrate that inactivating Vegfr3 in the Tbx1 expression domain on a Tbx1 mutant background enhances brain vessel branching and filopodia formation, whereas increasing Vegfr3 expression in this domain fully rescued these phenotypes. Similar results were obtained using an in vitro model of endothelial tubulogenesis. Overall, the results of this study provide genetic evidence that VEGFR3 is a regulator of early vessel branching and filopodia formation in the mouse brain and is a likely mediator of the brain vascular phenotype caused by Tbx1 loss of function.
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Affiliation(s)
- Sara Cioffi
- Institute of Genetics and Biophysics "ABT," CNR, Naples, Italy
| | - Gemma Flore
- Institute of Genetics and Biophysics "ABT," CNR, Naples, Italy
| | | | - Marchesa Bilio
- Institute of Genetics and Biophysics "ABT," CNR, Naples, Italy
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Bautch VL, Mukouyama YS. The Beauty and Complexity of Blood Vessel Patterning. Cold Spring Harb Perspect Med 2022; 12:a041167. [PMID: 35379659 PMCID: PMC9619359 DOI: 10.1101/cshperspect.a041167] [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] [Indexed: 11/24/2022]
Abstract
This review highlights new concepts in vascular patterning in the last 10 years, with emphasis on its beauty and complexity. Endothelial cell signaling pathways that respond to molecular or mechanical signals are described, and examples of vascular patterning that use these pathways in brain, skin, heart, and kidney are highlighted. The pathological consequences of patterning loss are discussed in the context of arteriovenous malformations (AVMs), and prospects for the next 10 years presented.
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Affiliation(s)
- Victoria L Bautch
- Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
| | - Yoh-Suke Mukouyama
- Laboratory of Stem Cell and Neuro-Vascular Biology, Cell and Development Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
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Zhang S, Gan L, Cao F, Wang H, Gong P, Ma C, Ren L, Lin Y, Lin X. The barrier and interface mechanisms of the brain barrier, and brain drug delivery. Brain Res Bull 2022; 190:69-83. [PMID: 36162603 DOI: 10.1016/j.brainresbull.2022.09.017] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 08/25/2022] [Accepted: 09/20/2022] [Indexed: 11/26/2022]
Abstract
Three different barriers are formed between the cerebrovascular and the brain parenchyma: the blood-brain barrier (BBB), the blood-cerebrospinal fluid barrier (BCSFB), and the cerebrospinal fluid-brain barrier (CBB). The BBB is the main regulator of blood and central nervous system (CNS) material exchange. The semipermeable nature of the BBB limits the passage of larger molecules and hydrophilic small molecules, Food and Drug Administration (FDA)-approved drugs for the CNS have been generally limited to lipid-soluble small molecules. Although the complexity of the BBB affects CNS drug delivery, understanding the composition and function of the BBB can provide a platform for the development of new methods for CNS drug delivery. This review summarizes the classification of the brain barrier, the composition and role of the basic structures of the BBB, and the transport, barrier, and destruction mechanisms of the BBB; discusses the advantages and disadvantages of different drug delivery methods and prospects for future drug delivery strategies.
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Affiliation(s)
- Shanshan Zhang
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310005, Zhejiang Province, China
| | - Lin Gan
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, China
| | - Fengye Cao
- Yiyang The First Hospital of Traditional Chinese Medicine, Yiyang, Hunan Province, 413000, China
| | - Hao Wang
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, China
| | - Peng Gong
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, China
| | - Congcong Ma
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, China
| | - Li Ren
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, China
| | - Yubo Lin
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, China
| | - Xianming Lin
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, China.
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Sato Y, Falcone-Juengert J, Tominaga T, Su H, Liu J. Remodeling of the Neurovascular Unit Following Cerebral Ischemia and Hemorrhage. Cells 2022; 11:2823. [PMID: 36139398 PMCID: PMC9496956 DOI: 10.3390/cells11182823] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/18/2022] [Accepted: 08/30/2022] [Indexed: 11/23/2022] Open
Abstract
Formulated as a group effort of the stroke community, the transforming concept of the neurovascular unit (NVU) depicts the structural and functional relationship between brain cells and the vascular structure. Composed of both neural and vascular elements, the NVU forms the blood-brain barrier that regulates cerebral blood flow to meet the oxygen demand of the brain in normal physiology and maintain brain homeostasis. Conversely, the dysregulation and dysfunction of the NVU is an essential pathological feature that underlies neurological disorders spanning from chronic neurodegeneration to acute cerebrovascular events such as ischemic stroke and cerebral hemorrhage, which were the focus of this review. We also discussed how common vascular risk factors of stroke predispose the NVU to pathological changes. We synthesized existing literature and first provided an overview of the basic structure and function of NVU, followed by knowledge of how these components remodel in response to ischemic stroke and brain hemorrhage. A greater understanding of the NVU dysfunction and remodeling will enable the design of targeted therapies and provide a valuable foundation for relevant research in this area.
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Affiliation(s)
- Yoshimichi Sato
- Department of Neurological Surgery, UCSF, San Francisco, CA 94158, USA
- Department of Neurological Surgery, SFVAMC, San Francisco, CA 94158, USA
- Department of Neurosurgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Jaime Falcone-Juengert
- Department of Neurological Surgery, UCSF, San Francisco, CA 94158, USA
- Department of Neurological Surgery, SFVAMC, San Francisco, CA 94158, USA
| | - Teiji Tominaga
- Department of Neurosurgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Hua Su
- Department of Anesthesia, UCSF, San Francisco, CA 94143, USA
- Center for Cerebrovascular Research, UCSF, San Francisco, CA 94143, USA
| | - Jialing Liu
- Department of Neurological Surgery, UCSF, San Francisco, CA 94158, USA
- Department of Neurological Surgery, SFVAMC, San Francisco, CA 94158, USA
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10
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Rashbrook VS, Brash JT, Ruhrberg C. Cre toxicity in mouse models of cardiovascular physiology and disease. NATURE CARDIOVASCULAR RESEARCH 2022; 1:806-816. [PMID: 37692772 PMCID: PMC7615056 DOI: 10.1038/s44161-022-00125-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/27/2022] [Indexed: 09/12/2023]
Abstract
The Cre-LoxP system provides a widely used method for studying gene requirements in the mouse as the main mammalian genetic model organism. To define the molecular and cellular mechanisms that underlie cardiovascular development, function and disease, various mouse strains have been engineered that allow Cre-LoxP-mediated gene targeting within specific cell types of the cardiovascular system. Despite the usefulness of this system, evidence is accumulating that Cre activity can have toxic effects in cells, independently of its ability to recombine pairs of engineered LoxP sites in target genes. Here, we have gathered published evidence for Cre toxicity in cells and tissues relevant to cardiovascular biology and provide an overview of mechanisms proposed to underlie Cre toxicity. Based on this knowledge, we propose that each study utilising the Cre-LoxP system to investigate gene function in the cardiovascular system should incorporate appropriate controls to account for Cre toxicity.
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Affiliation(s)
- Victoria S. Rashbrook
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK
| | - James T. Brash
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK
| | - Christiana Ruhrberg
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK
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11
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Fóthi Á, Pintér C, Pollner P, Lőrincz A. Peripheral gene interactions define interpretable clusters of core ASD genes in a network-based investigation of the omnigenic theory. NPJ Syst Biol Appl 2022; 8:28. [PMID: 35948596 PMCID: PMC9365765 DOI: 10.1038/s41540-022-00240-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: 11/19/2021] [Accepted: 07/20/2022] [Indexed: 11/23/2022] Open
Abstract
According to the recently proposed omnigenic theory, all expressed genes in a relevant tissue are contributing directly or indirectly to the manifestation of complex disorders such as autism. Thus, holistic approaches can be complementary in studying genetics of these complex disorders to focusing on a limited number of candidate genes. Gene interaction networks can be used for holistic studies of the omnigenic nature of autism. We used Louvain clustering on tissue-specific gene interaction networks and their subgraphs exclusively containing autism-related genes to study the effects of peripheral gene interactions. We observed that the autism gene clusters are significantly weaker connected to each other and the peripheral genes in non-neuronal tissues than in brain-related tissues. The biological functions of the brain clusters correlated well with previous findings on autism, such as synaptic signaling, regulation of DNA methylation, or regulation of lymphocyte activation, however, on the other tissues they did not enrich as significantly. Furthermore, ASD subjects with disruptive mutations in specific gene clusters show phenotypical differences compared to other disruptive variants carrying ASD individuals. Our results strengthen the omnigenic theory and can advance our understanding of the genetic background of autism.
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Affiliation(s)
- Ábel Fóthi
- Department of Artificial Intelligence, Faculty of Informatics, Eötvös Loránd University, Budapest, Hungary.
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary.
- Institute of Archaeogenomics, Research Centre for the Humanities, Budapest, Hungary.
| | - Csaba Pintér
- Department of Artificial Intelligence, Faculty of Informatics, Eötvös Loránd University, Budapest, Hungary
| | - Péter Pollner
- MTA-ELTE Statistical and Biological Physics Research Group, Eötvös Loránd Research Network (ELKH), Department of Biological Physics, Eötvös University, Budapest, Hungary
- Health Services Management Training Centre, Semmelweis University, Budapest, Hungary
| | - András Lőrincz
- Department of Artificial Intelligence, Faculty of Informatics, Eötvös Loránd University, Budapest, Hungary
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12
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Matsuoka RL, Buck LD, Vajrala KP, Quick RE, Card OA. Historical and current perspectives on blood endothelial cell heterogeneity in the brain. Cell Mol Life Sci 2022; 79:372. [PMID: 35726097 PMCID: PMC9209386 DOI: 10.1007/s00018-022-04403-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/18/2022] [Accepted: 05/25/2022] [Indexed: 11/28/2022]
Abstract
Dynamic brain activity requires timely communications between the brain parenchyma and circulating blood. Brain-blood communication is facilitated by intricate networks of brain vasculature, which display striking heterogeneity in structure and function. This vascular cell heterogeneity in the brain is fundamental to mediating diverse brain functions and has long been recognized. However, the molecular basis of this biological phenomenon has only recently begun to be elucidated. Over the past century, various animal species and in vitro systems have contributed to the accumulation of our fundamental and phylogenetic knowledge about brain vasculature, collectively advancing this research field. Historically, dye tracer and microscopic observations have provided valuable insights into the anatomical and functional properties of vasculature across the brain, and these techniques remain an important approach. Additionally, recent advances in molecular genetics and omics technologies have revealed significant molecular heterogeneity within brain endothelial and perivascular cell types. The combination of these conventional and modern approaches has enabled us to identify phenotypic differences between healthy and abnormal conditions at the single-cell level. Accordingly, our understanding of brain vascular cell states during physiological, pathological, and aging processes has rapidly expanded. In this review, we summarize major historical advances and current knowledge on blood endothelial cell heterogeneity in the brain, and discuss important unsolved questions in the field.
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Affiliation(s)
- Ryota L Matsuoka
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. .,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA.
| | - Luke D Buck
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA
| | - Keerti P Vajrala
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA.,Kansas City University College of Osteopathic Medicine, Kansas City, MO 64106, USA
| | - Rachael E Quick
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA
| | - Olivia A Card
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA
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13
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Abstract
The brain harbors a unique ability to, figuratively speaking, shift its gears. During wakefulness, the brain is geared fully toward processing information and behaving, while homeostatic functions predominate during sleep. The blood-brain barrier establishes a stable environment that is optimal for neuronal function, yet the barrier imposes a physiological problem; transcapillary filtration that forms extracellular fluid in other organs is reduced to a minimum in brain. Consequently, the brain depends on a special fluid [the cerebrospinal fluid (CSF)] that is flushed into brain along the unique perivascular spaces created by astrocytic vascular endfeet. We describe this pathway, coined the term glymphatic system, based on its dependency on astrocytic vascular endfeet and their adluminal expression of aquaporin-4 water channels facing toward CSF-filled perivascular spaces. Glymphatic clearance of potentially harmful metabolic or protein waste products, such as amyloid-β, is primarily active during sleep, when its physiological drivers, the cardiac cycle, respiration, and slow vasomotion, together efficiently propel CSF inflow along periarterial spaces. The brain's extracellular space contains an abundance of proteoglycans and hyaluronan, which provide a low-resistance hydraulic conduit that rapidly can expand and shrink during the sleep-wake cycle. We describe this unique fluid system of the brain, which meets the brain's requisites to maintain homeostasis similar to peripheral organs, considering the blood-brain-barrier and the paths for formation and egress of the CSF.
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Affiliation(s)
- Martin Kaag Rasmussen
- Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Humberto Mestre
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York
| | - Maiken Nedergaard
- Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York
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14
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D'Amico G, Ruhrberg C. The Embryonic Mouse Hindbrain Model to Study Sprouting Angiogenesis In Vivo. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2441:3-18. [PMID: 35099724 DOI: 10.1007/978-1-0716-2059-5_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Blood vessel growth is a fundamental process for organ development and wound healing but is also associated with ischemic diseases and cancer. The growth of new blood vessels from preexisting vasculature, termed sprouting angiogenesis, is the predominant mode of blood vessel growth in central nervous system vascularization and pathological vessel growth. Accordingly, studying the molecular and cellular mechanisms of angiogenesis holds the promise to find novel therapeutic targets to stimulate new vessel formation in ischemic tissues or inhibit pathological vessel growth in disease. The embryonic mouse hindbrain provides an excellent model to study sprouting angiogenesis in vivo by histochemical or fluorescent wholemount immunolabeling, thus allowing high-resolution image capture of nascent vasculature and subsequent quantification of relevant angiogenic parameters. This chapter describes how to use the mouse embryonic hindbrain as a model to study physiological angiogenesis, including detailed protocols for hindbrain dissection, wholemount staining, and angiogenic parameters analysis.
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Affiliation(s)
- Gabriela D'Amico
- UCL Institute of Ophthalmology, University College London, London, UK
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15
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Helmbacher F. Astrocyte-intrinsic and -extrinsic Fat1 activities regulate astrocyte development and angiogenesis in the retina. Development 2022; 149:274046. [PMID: 35050341 DOI: 10.1242/dev.192047] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 12/13/2021] [Indexed: 01/25/2023]
Abstract
Angiogenesis is a stepwise process leading to blood vessel formation. In the vertebrate retina, endothelial cells are guided by astrocytes migrating along the inner surface, and the two processes are coupled by a tightly regulated cross-talks between the two cell types. Here, I have investigated how the FAT1 cadherin, a regulator of tissue morphogenesis that governs tissue cross-talk, influences retinal vascular development. Late-onset Fat1 inactivation in the neural lineage in mice, by interfering with astrocyte progenitor migration polarity and maturation, delayed postnatal retinal angiogenesis, leading to persistent vascular abnormalities in adult retinas. Impaired astrocyte migration and polarity were not associated with alterations of retinal ganglion cell axonal trajectories or of the inner limiting membrane. In contrast, inducible Fat1 ablation in postnatal astrocytes was sufficient to alter their migration polarity and proliferation. Altogether, this study uncovers astrocyte-intrinsic and -extrinsic Fat1 activities that influence astrocyte migration polarity, proliferation and maturation, disruption of which impacts retinal vascular development and maintenance.
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Affiliation(s)
- Françoise Helmbacher
- Aix Marseille Univ, CNRS, IBDM UMR 7288, Parc Scientifique de Luminy, Case 907, 13288 Marseille, France
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16
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Potjewyd G, Kellett K, Hooper N. 3D hydrogel models of the neurovascular unit to investigate blood-brain barrier dysfunction. Neuronal Signal 2021; 5:NS20210027. [PMID: 34804595 PMCID: PMC8579151 DOI: 10.1042/ns20210027] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 12/16/2022] Open
Abstract
The neurovascular unit (NVU), consisting of neurons, glial cells, vascular cells (endothelial cells, pericytes and vascular smooth muscle cells (VSMCs)) together with the surrounding extracellular matrix (ECM), is an important interface between the peripheral blood and the brain parenchyma. Disruption of the NVU impacts on blood-brain barrier (BBB) regulation and underlies the development and pathology of multiple neurological disorders, including stroke and Alzheimer's disease (AD). The ability to differentiate induced pluripotent stem cells (iPSCs) into the different cell types of the NVU and incorporate them into physical models provides a reverse engineering approach to generate human NVU models to study BBB function. To recapitulate the in vivo situation such NVU models must also incorporate the ECM to provide a 3D environment with appropriate mechanical and biochemical cues for the cells of the NVU. In this review, we provide an overview of the cells of the NVU and the surrounding ECM, before discussing the characteristics (stiffness, functionality and porosity) required of hydrogels to mimic the ECM when incorporated into in vitro NVU models. We summarise the approaches available to measure BBB functionality and present the techniques in use to develop robust and translatable models of the NVU, including transwell models, hydrogel models, 3D-bioprinting, microfluidic models and organoids. The incorporation of iPSCs either without or with disease-specific genetic mutations into these NVU models provides a platform in which to study normal and disease mechanisms, test BBB permeability to drugs, screen for new therapeutic targets and drugs or to design cell-based therapies.
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Affiliation(s)
- Geoffrey Potjewyd
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, U.K
| | - Katherine A.B. Kellett
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, U.K
| | - Nigel M. Hooper
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, U.K
- Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and University of Manchester, Manchester, U.K
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17
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Lee M, Kannan S, Muniraj G, Rosa V, Lu WF, Fuh JYH, Sriram G, Cao T. Two-Photon Fluorescence Microscopy and Applications in Angiogenesis and Related Molecular Events. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:926-937. [PMID: 34541887 DOI: 10.1089/ten.teb.2021.0140] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The role of angiogenesis in health and disease have gained considerable momentum in recent years. Visualizing angiogenic patterns and associated events of surrounding vascular beds in response to therapeutic and laboratory-grade biomolecules have become a commonplace in regenerative medicine and the biosciences. To aid imaging investigations in angiogenesis, the two-photon excitation fluorescence microscopy (2PEF), or multiphoton fluorescence microscopy is increasingly utilized in scientific investigations. The 2PEF microscope confers several distinct imaging advantages over other fluorescence excitation microscopy techniques - for the observation of in-depth, three-dimensional vascularity in a variety of tissue formats, including fixed tissue specimens and in vivo vasculature in live specimens. Understanding morphological and subcellular changes that occur in cells and tissues during angiogenesis will provide insights to behavioral responses in diseased states, advance the engineering of physiologically-relevant tissue models and provide biochemical clues for the design of therapeutic strategies. We review the applicability and limitations of the 2PEF microscope on the biophysical and molecular-level signatures of angiogenesis in various tissue models. Imaging techniques and strategies for best practices in 2PEF microscopy will be reviewed.
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Affiliation(s)
- Marcus Lee
- Faculty of Dentistry, National University of Singapore, Singapore, Singapore
| | - Sathya Kannan
- Faculty of Dentistry, National University of Singapore, Singapore, Singapore
| | - Giridharan Muniraj
- Faculty of Dentistry, National University of Singapore, Singapore, Singapore
| | - Vinicius Rosa
- Faculty of Dentistry, National University of Singapore, Singapore, Singapore
| | - Wen Feng Lu
- Department of Mechanical Engineering, National University of Singapore, Singapore, Singapore
| | - Jerry Y H Fuh
- Department of Mechanical Engineering, National University of Singapore, Singapore, Singapore
| | - Gopu Sriram
- Faculty of Dentistry, National University of Singapore, Singapore, Singapore
| | - Tong Cao
- Faculty of Dentistry, National University of Singapore, Singapore, Singapore
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18
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Stackhouse TL, Mishra A. Neurovascular Coupling in Development and Disease: Focus on Astrocytes. Front Cell Dev Biol 2021; 9:702832. [PMID: 34327206 PMCID: PMC8313501 DOI: 10.3389/fcell.2021.702832] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/09/2021] [Indexed: 12/14/2022] Open
Abstract
Neurovascular coupling is a crucial mechanism that matches the high energy demand of the brain with a supply of energy substrates from the blood. Signaling within the neurovascular unit is responsible for activity-dependent changes in cerebral blood flow. The strength and reliability of neurovascular coupling form the basis of non-invasive human neuroimaging techniques, including blood oxygen level dependent (BOLD) functional magnetic resonance imaging. Interestingly, BOLD signals are negative in infants, indicating a mismatch between metabolism and blood flow upon neural activation; this response is the opposite of that observed in healthy adults where activity evokes a large oversupply of blood flow. Negative neurovascular coupling has also been observed in rodents at early postnatal stages, further implying that this is a process that matures during development. This rationale is consistent with the morphological maturation of the neurovascular unit, which occurs over a similar time frame. While neurons differentiate before birth, astrocytes differentiate postnatally in rodents and the maturation of their complex morphology during the first few weeks of life links them with synapses and the vasculature. The vascular network is also incomplete in neonates and matures in parallel with astrocytes. Here, we review the timeline of the structural maturation of the neurovascular unit with special emphasis on astrocytes and the vascular tree and what it implies for functional maturation of neurovascular coupling. We also discuss similarities between immature astrocytes during development and reactive astrocytes in disease, which are relevant to neurovascular coupling. Finally, we close by pointing out current gaps in knowledge that must be addressed to fully elucidate the mechanisms underlying neurovascular coupling maturation, with the expectation that this may also clarify astrocyte-dependent mechanisms of cerebrovascular impairment in neurodegenerative conditions in which reduced or negative neurovascular coupling is noted, such as stroke and Alzheimer’s disease.
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Affiliation(s)
- Teresa L Stackhouse
- Department of Neurology, Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR, United States
| | - Anusha Mishra
- Department of Neurology, Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR, United States.,Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, OR, United States
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19
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Mentor S, Fisher D. High-Resolution Insights Into the in vitro Developing Blood-Brain Barrier: Novel Morphological Features of Endothelial Nanotube Function. Front Neuroanat 2021; 15:661065. [PMID: 34248507 PMCID: PMC8267063 DOI: 10.3389/fnana.2021.661065] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/21/2021] [Indexed: 12/28/2022] Open
Abstract
High-resolution electron microscopy (HREM) imaging of the in vitro blood-brain barrier (BBB), is a promising modality for investigating the dynamic morphological interplay underpinning BBB development. The successful establishment of BBB integrity is grounded in the brain endothelial cells (BEC’s) ability to occlude its paracellular spaces of brain capillaries through the expression of the intercellular tight junction (TJ) proteins. The impermeability of these paracellular spaces are crucial in the regulation of transcellular transport systems to achieve homeostasis of the central nervous system. To-date research describing morphologically, the dynamics by which TJ interaction is orchestrated to successfully construct a specialized barrier remains undescribed. In this study, the application of HREM illuminates the novel, dynamic and highly restrictive BEC paracellular pathway which is founded based on lateral membrane alignment which is the functional imperative for the mechanical juxtapositioning of TJ zones that underpin molecular bonding and sealing of the paracellular space. For the first time, we report on the secretion of a basement membrane in vitro, which allow BECs to orientate themselves into distinct basolateral and apicolateral domains and establish a 3-dimensional BEC construct. We report for the first time, on the expression of nanovesicles bound to the plasma membrane surfaces of the BECs. These membrane-bound vesicles are reported to possess an array of DNA/RNA constituents and chemotaxic properties affecting the formation of nanotubes that span the paracellular space between BECs, facilitating BBB construction, alluding to a functional role in mediating cell-to-cell communication. This study suggests that novel, ultrathin nanotubular (NT) structures are involved in functional roles in bringing into alignment the paracellular space of BECs. Immortalized mouse BECs (b.End3, b.End5) and primary rat cardiac microvascular ECs were used to further validate the in vitro BBB model by profiling variances in peripheral EC monolayer development. These cardiac capillary ECs presented with an opposite topographical profile: large fenestra and intercellular spaces, devoid of morphological ultrastructures. This comparative study alludes to the role of NT facilitation in TJ-induced hemifusion of apicolateral BEC membranes, as a structural event forming the basis for establishing a polarized BBB.
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Affiliation(s)
- Shireen Mentor
- Neurobiology Research Group, Department of Medical Biosciences, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa
| | - David Fisher
- Neurobiology Research Group, Department of Medical Biosciences, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa.,Adjunct Professor in School of Health Professions, University of Missouri, Columbia, MO, United States
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20
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Sun Q, Xu X, Wang T, Xu Z, Lu X, Li X, Chen G. Neurovascular Units and Neural-Glia Networks in Intracerebral Hemorrhage: from Mechanisms to Translation. Transl Stroke Res 2021; 12:447-460. [PMID: 33629275 DOI: 10.1007/s12975-021-00897-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 02/07/2021] [Accepted: 02/09/2021] [Indexed: 12/20/2022]
Abstract
Intracerebral hemorrhage (ICH), the most lethal type of stroke, often leads to poor outcomes in the clinic. Due to the complex mechanisms and cell-cell crosstalk during ICH, the neurovascular unit (NVU) was proposed to serve as a promising therapeutic target for ICH research. This review aims to summarize the development of pathophysiological shifts in the NVU and neural-glia networks after ICH. In addition, potential targets for ICH therapy are discussed in this review. Beyond cerebral blood flow, the NVU also plays an important role in protecting neurons, maintaining central nervous system (CNS) homeostasis, coordinating neuronal activity among supporting cells, forming and maintaining the blood-brain barrier (BBB), and regulating neuroimmune responses. During ICH, NVU dysfunction is induced, along with neuronal cell death, microglia and astrocyte activation, endothelial cell (EC) and tight junction (TJ) protein damage, and BBB disruption. In addition, it has been shown that certain targets and candidates can improve ICH-induced secondary brain injury based on an NVU and neural-glia framework. Moreover, therapeutic approaches and strategies for ICH are discussed.
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Affiliation(s)
- Qing Sun
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, China
| | - Xiang Xu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, China
| | - Tianyi Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, China
| | - Zhongmou Xu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, China
| | - Xiaocheng Lu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, China.
| | - Xiang Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, China.
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, China
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21
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Gupta A, Rarick KR, Ramchandran R. Established, New and Emerging Concepts in Brain Vascular Development. Front Physiol 2021; 12:636736. [PMID: 33643074 PMCID: PMC7907611 DOI: 10.3389/fphys.2021.636736] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/15/2021] [Indexed: 12/20/2022] Open
Abstract
In this review, we discuss the state of our knowledge as it relates to embryonic brain vascular patterning in model systems zebrafish and mouse. We focus on the origins of endothelial cell and the distinguishing features of brain endothelial cells compared to non-brain endothelial cells, which is revealed by single cell RNA-sequencing methodologies. We also discuss the cross talk between brain endothelial cells and neural stem cells, and their effect on each other. In terms of mechanisms, we focus exclusively on Wnt signaling and the recent developments associated with this signaling network in brain vascular patterning, and the benefits and challenges associated with strategies for targeting the brain vasculature. We end the review with a discussion on the emerging areas of meningeal lymphatics, endothelial cilia biology and novel cerebrovascular structures identified in vertebrates.
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Affiliation(s)
- Ankan Gupta
- Department of Pediatrics, Division of Neonatology, Developmental Vascular Biology Program, Children’s Research Institute (CRI), Medical College of Wisconsin, Milwaukee, WI, United States
| | - Kevin R. Rarick
- Department of Pediatrics, Division of Critical Care, Children’s Research Institute (CRI), Medical College of Wisconsin, Milwaukee, WI, United States
| | - Ramani Ramchandran
- Department of Pediatrics, Division of Neonatology, Developmental Vascular Biology Program, Children’s Research Institute (CRI), Medical College of Wisconsin, Milwaukee, WI, United States
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22
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Gama Sosa MA, De Gasperi R, Perez GM, Hof PR, Elder GA. Hemovasculogenic origin of blood vessels in the developing mouse brain. J Comp Neurol 2021; 529:340-366. [PMID: 32415669 DOI: 10.1002/cne.24951] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 05/05/2020] [Accepted: 05/08/2020] [Indexed: 01/20/2023]
Abstract
Vascular structures in the developing brain are thought to form via angiogenesis from preformed blood vessels in the cephalic mesenchyme. Immunohistochemical studies of developing mouse brain from E10.5 to E13.5 revealed the presence of avascular blood islands of primitive erythroid cells expressing hemangioblast markers (Flk1, Tal1/Scl1, platelet endothelial cell adhesion molecule 1, vascular endothelial-cadherin, and CD34) and an endothelial marker recognized by Griffonia simplicifolia isolectin B4 (IB4) in the cephalic mesenchyme. These cells formed a perineural vascular plexus from which angiogenic sprouts originated and penetrated the neuroepithelium. In addition, avascular isolated cells expressing primitive erythroid, hemangioblast and endothelial makers were visible in the neuroepithelium where they generated vasculogenic and hemogenic foci. From E10.5 to E13.5, these vasculogenic foci were a source of new blood vessel formation in the developing brain. In vitro, cultured E13.5 brain endothelial cells contained hemogenic endothelial cells capable of generating erythroid cells. Similar cells were present in primary cultures of dissociated cells from E10.5 embryonic head. Our results provide new evidence that the brain vasculature, like that of the yolk sac and the eye choriocapillaris and hyaloid vascular systems, develops at least in part via hemovasculogenesis, a process in which vasculogenesis and hematopoiesis occur simultaneously.
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Affiliation(s)
- Miguel A Gama Sosa
- General Medical Research Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, New York, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Rita De Gasperi
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Research and Development Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, New York, USA
| | - Gissel M Perez
- Research and Development Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, New York, USA
| | - Patrick R Hof
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Geriatrics and Palliative Care, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Gregory A Elder
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, New York, USA
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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23
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Dash S, Bhatt S, Sandell LL, Seidel CW, Ahn Y, Krumlauf RE, Trainor PA. The Mediator Subunit, Med23 Is Required for Embryonic Survival and Regulation of Canonical WNT Signaling During Cranial Ganglia Development. Front Physiol 2020; 11:531933. [PMID: 33192541 PMCID: PMC7642510 DOI: 10.3389/fphys.2020.531933] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 09/16/2020] [Indexed: 11/13/2022] Open
Abstract
Development of the vertebrate head is a complex and dynamic process, which requires integration of all three germ layers and their derivatives. Of special importance are ectoderm-derived cells that form the cranial placodes, which then differentiate into the cranial ganglia and sensory organs. Critical to a fully functioning head, defects in cranial placode and sensory organ development can result in congenital craniofacial anomalies. In a forward genetic screen aimed at identifying novel regulators of craniofacial development, we discovered an embryonically lethal mouse mutant, snouty, which exhibits malformation of the facial prominences, cranial nerves and vasculature. The snouty mutation was mapped to a single nucleotide change in a ubiquitously expressed gene, Med23, which encodes a subunit of the global transcription co-factor complex, Mediator. Phenotypic analyses revealed that the craniofacial anomalies, particularly of the cranial ganglia, were caused by a failure in the proper specification of cranial placode neuronal precursors. Molecular analyses determined that defects in cranial placode neuronal differentiation in Med23 sn/sn mutants were associated with elevated WNT/β-catenin signaling, which can be partially rescued through combined Lrp6 and Wise loss-of-function. Our work therefore reveals a surprisingly tissue specific role for the ubiquitously expressed mediator complex protein Med23 in placode differentiation during cranial ganglia development. This highlights the importance of coupling general transcription to the regulation of WNT signaling during embryogenesis.
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Affiliation(s)
- Soma Dash
- Stowers Institute for Medical Research, Kansas City, MO, United States
| | - Shachi Bhatt
- Stowers Institute for Medical Research, Kansas City, MO, United States.,Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Lisa L Sandell
- Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, KY, United States
| | | | - Youngwook Ahn
- Stowers Institute for Medical Research, Kansas City, MO, United States
| | - Robb E Krumlauf
- Stowers Institute for Medical Research, Kansas City, MO, United States.,Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Paul A Trainor
- Stowers Institute for Medical Research, Kansas City, MO, United States.,Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, United States
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24
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Boleti APDA, Frihling BEF, E Silva PS, Cardoso PHDO, de Moraes LFRN, Rodrigues TAA, Biembengute MEF, Koolen HHF, Migliolo L. Biochemical aspects and therapeutic mechanisms of cannabidiol in epilepsy. Neurosci Biobehav Rev 2020; 132:1214-1228. [PMID: 33031814 DOI: 10.1016/j.neubiorev.2020.09.027] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/23/2020] [Accepted: 09/26/2020] [Indexed: 12/12/2022]
Abstract
Epilepsy is a chronic neurological disease characterized by recurrent epileptic seizures. Studies have shown the complexity of epileptogenesis and ictogenesis, in which immunological processes and epigenetic and structural changes in neuronal tissues have been identified as triggering epilepsy. Cannabidiol (CBD) is a major active component of the Cannabis plant and the source of CBD-enriched products for the treatment of epilepsy and associated diseases. In this review, we provide an up-to-date discussion on cellular and molecular mechanisms triggered during epilepsy crises, and the phytochemical characteristics of CBD that make it an attractive candidate for controlling rare syndromes, with excellent therapeutic properties. We also discuss possible CBD anticonvulsant mechanisms and molecular targets in neurodegenerative disorders and epilepsy. Based on these arguments, we conclude that CBD presents a biotecnological potential in the anticonvulsant process, including decreasing dependence on health care in hospitals, and could make the patient's life more stable, with regard to neurological conditions.
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Affiliation(s)
- Ana Paula de A Boleti
- S-InovaBiotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, 79117-900, Campo Grande, MS, Brazil
| | - Breno Emanuel F Frihling
- S-InovaBiotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, 79117-900, Campo Grande, MS, Brazil
| | - Patrícia Souza E Silva
- S-InovaBiotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, 79117-900, Campo Grande, MS, Brazil
| | - Pedro Henrique de O Cardoso
- S-InovaBiotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, 79117-900, Campo Grande, MS, Brazil
| | - Luiz Filipe R N de Moraes
- S-InovaBiotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, 79117-900, Campo Grande, MS, Brazil
| | - Thiago Antônio A Rodrigues
- S-InovaBiotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, 79117-900, Campo Grande, MS, Brazil
| | | | - Hector Henrique F Koolen
- Grupo de Estudos em Metabolômica e Espectrometria de Massas, Universidade do Estado do Amazonas - UEA, Manaus, Brazil
| | - Ludovico Migliolo
- S-InovaBiotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, 79117-900, Campo Grande, MS, Brazil; Programa de Pós-graduação em Biologia Celular e Molecular, Universidade Federal da Paraíba, João Pessoa, Brazil; Programa de Pós-graduação em Bioquímica, Universidade Federal do Rio Grande do Norte, Natal, Brazil.
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25
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Segarra M, Aburto MR, Hefendehl J, Acker-Palmer A. Neurovascular Interactions in the Nervous System. Annu Rev Cell Dev Biol 2020; 35:615-635. [PMID: 31590587 DOI: 10.1146/annurev-cellbio-100818-125142] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Molecular cross talk between the nervous and vascular systems is necessary to maintain the correct coupling of organ structure and function. Molecular pathways shared by both systems are emerging as major players in the communication of the neuronal compartment with the endothelium. Here we review different aspects of this cross talk and how vessels influence the development and homeostasis of the nervous system. Beyond the classical role of the vasculature as a conduit to deliver oxygen and metabolites needed for the energy-demanding neuronal compartment, vessels emerge as powerful signaling systems that control and instruct a variety of cellular processes during the development of neurons and glia, such as migration, differentiation, and structural connectivity. Moreover, a broad spectrum of mild to severe vascular dysfunctions occur in various pathologies of the nervous system, suggesting that mild structural and functional changes at the neurovascular interface may underlie cognitive decline in many of these pathological conditions.
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Affiliation(s)
- Marta Segarra
- Neuro and Vascular Guidance, Buchmann Institute for Molecular Life Sciences, University of Frankfurt, D-60438 Frankfurt am Main, Germany; , .,Institute of Cell Biology and Neuroscience, University of Frankfurt, D-60438 Frankfurt am Main, Germany
| | - Maria R Aburto
- Neuro and Vascular Guidance, Buchmann Institute for Molecular Life Sciences, University of Frankfurt, D-60438 Frankfurt am Main, Germany; , .,Institute of Cell Biology and Neuroscience, University of Frankfurt, D-60438 Frankfurt am Main, Germany
| | - Jasmin Hefendehl
- Neurovascular Disorders, Buchmann Institute for Molecular Life Sciences, University of Frankfurt, D-60438 Frankfurt am Main, Germany.,Institute of Cell Biology and Neuroscience, University of Frankfurt, D-60438 Frankfurt am Main, Germany
| | - Amparo Acker-Palmer
- Neuro and Vascular Guidance, Buchmann Institute for Molecular Life Sciences, University of Frankfurt, D-60438 Frankfurt am Main, Germany; , .,Institute of Cell Biology and Neuroscience, University of Frankfurt, D-60438 Frankfurt am Main, Germany.,Max Planck Institute for Brain Research, D-60438 Frankfurt am Main, Germany
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26
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Salick MR, Lubeck E, Riesselman A, Kaykas A. The future of cerebral organoids in drug discovery. Semin Cell Dev Biol 2020; 111:67-73. [PMID: 32654970 DOI: 10.1016/j.semcdb.2020.05.024] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 04/28/2020] [Accepted: 05/27/2020] [Indexed: 12/27/2022]
Abstract
Until the discovery of human embryonic stem cells and human induced pluripotent stem cells, biotechnology companies were severely limited in the number of human tissues that they could model in large-scale in vitro studies. Until this point, companies have been limited to immortalized cancer lines or a small number of primary cell types that could be extracted and expanded. Nowadays, protocols continue to be developed in the stem cell field, enabling researchers to model an ever-growing library of cell types in controlled, large-scale screens. One differentiation method in particular- cerebral organoids- shows substantial potential in the field of neuroscience and developmental neurobiology. Cerebral organoid technology is still in an early phase of development, and there are several challenges that are currently being addressed by academic and industrial researchers alike. Here we briefly describe some of the early adopters of cerebral organoids, several of the challenges that they are likely facing, and various technologies that are currently being implemented to overcome them.
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Affiliation(s)
- Max R Salick
- insitro 279 East Grand Avenue South, San Francisco CA, United States
| | - Eric Lubeck
- insitro 279 East Grand Avenue South, San Francisco CA, United States
| | - Adam Riesselman
- insitro 279 East Grand Avenue South, San Francisco CA, United States
| | - Ajamete Kaykas
- insitro 279 East Grand Avenue South, San Francisco CA, United States
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27
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Brash JT, Bolton RL, Rashbrook VS, Denti L, Kubota Y, Ruhrberg C. Tamoxifen-Activated CreERT Impairs Retinal Angiogenesis Independently of Gene Deletion. Circ Res 2020; 127:849-850. [PMID: 32635822 PMCID: PMC7447161 DOI: 10.1161/circresaha.120.317025] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- James T Brash
- From the UCL Institute of Ophthalmology, University College London, United Kingdom (J.T.B., R.L.B., V.S.R., L.D., C.R.)
| | - Rebecca L Bolton
- From the UCL Institute of Ophthalmology, University College London, United Kingdom (J.T.B., R.L.B., V.S.R., L.D., C.R.)
| | - Victoria S Rashbrook
- From the UCL Institute of Ophthalmology, University College London, United Kingdom (J.T.B., R.L.B., V.S.R., L.D., C.R.)
| | - Laura Denti
- From the UCL Institute of Ophthalmology, University College London, United Kingdom (J.T.B., R.L.B., V.S.R., L.D., C.R.)
| | - Yoshiaki Kubota
- Department of Anatomy, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan (Y.K.)
| | - Christiana Ruhrberg
- From the UCL Institute of Ophthalmology, University College London, United Kingdom (J.T.B., R.L.B., V.S.R., L.D., C.R.)
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28
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Glaesel K, May C, Marcus K, Matschke V, Theiss C, Theis V. miR-129-5p and miR-130a-3p Regulate VEGFR-2 Expression in Sensory and Motor Neurons during Development. Int J Mol Sci 2020; 21:ijms21113839. [PMID: 32481647 PMCID: PMC7312753 DOI: 10.3390/ijms21113839] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/15/2020] [Accepted: 05/21/2020] [Indexed: 01/23/2023] Open
Abstract
The wide-ranging influence of vascular endothelial growth factor (VEGF) within the central (CNS) and peripheral nervous system (PNS), for example through effects on axonal growth or neuronal cell survival, is mainly mediated by VEGF receptor 2 (VEGFR-2). However, the regulation of VEGFR-2 expression during development is not yet well understood. As microRNAs are considered to be key players during neuronal maturation and regenerative processes, we identified the two microRNAs (miRNAs)-miR-129-5p and miR-130a-3p-that may have an impact on VEGFR-2 expression in young and mature sensory and lower motor neurons. The expression level of VEGFR-2 was analyzed by using in situ hybridization, RT-qPCR, Western blot, and immunohistochemistry in developing rats. microRNAs were validated within the spinal cord and dorsal root ganglia. To unveil the molecular impact of our candidate microRNAs, dissociated cell cultures of sensory and lower motor neurons were transfected with mimics and inhibitors. We depicted age-dependent VEGFR-2 expression in sensory and lower motor neurons. In detail, in lower motor neurons, VEGFR-2 expression was significantly reduced during maturation, in conjunction with an increased level of miR-129-5p. In sensory dorsal root ganglia, VEGFR-2 expression increased during maturation and was accompanied by an overexpression of miR-130a-3p. In a second step, the functional significance of these microRNAs with respect to VEGFR-2 expression was proven. Whereas miR-129-5p seems to decrease VEGFR-2 expression in a direct manner in the CNS, miR-130a-3p might indirectly control VEGFR-2 expression in the PNS. A detailed understanding of genetic VEGFR-2 expression control might promote new strategies for the treatment of severe neurological diseases like ischemia or peripheral nerve injury.
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Affiliation(s)
- Kevin Glaesel
- Department of Cytology, Institute of Anatomy, Ruhr University Bochum, 44780 Bochum, Germany; (K.G.); (V.M.); (V.T.)
| | - Caroline May
- Medical Proteom-Center, Ruhr University Bochum, 44780 Bochum, NRW, Germany; (C.M.); (K.M.)
| | - Katrin Marcus
- Medical Proteom-Center, Ruhr University Bochum, 44780 Bochum, NRW, Germany; (C.M.); (K.M.)
| | - Veronika Matschke
- Department of Cytology, Institute of Anatomy, Ruhr University Bochum, 44780 Bochum, Germany; (K.G.); (V.M.); (V.T.)
| | - Carsten Theiss
- Department of Cytology, Institute of Anatomy, Ruhr University Bochum, 44780 Bochum, Germany; (K.G.); (V.M.); (V.T.)
- Correspondence: ; Tel.: +49-234-32-25018
| | - Verena Theis
- Department of Cytology, Institute of Anatomy, Ruhr University Bochum, 44780 Bochum, Germany; (K.G.); (V.M.); (V.T.)
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29
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Baruah J, Vasudevan A, Köhling R. Vascular Integrity and Signaling Determining Brain Development, Network Excitability, and Epileptogenesis. Front Physiol 2020; 10:1583. [PMID: 32038280 PMCID: PMC6987412 DOI: 10.3389/fphys.2019.01583] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 12/17/2019] [Indexed: 01/27/2023] Open
Abstract
Our understanding of the etiological mechanisms leading up to epilepsy has undergone radical changes over time due to more insights into the complexity of the disease. The traditional hypothesis emphasized network hyperexcitability and an imbalance of inhibition and excitation, eventually leading to seizures. In this context, the contribution of the vascular system, and particularly the interactions between blood vessels and neuronal tissue, came into focus only recently. Thus, one highly exciting causative or contributing factor of epileptogenesis is the disruption of the blood-brain barrier (BBB) in the context of not only posttraumatic epilepsy, but also other etiologies. This hypothesis is now recognized as a synergistic mechanism that can give rise to epilepsy, and BBB repair for restoration of cerebrovascular integrity is considered a therapeutic alternative. Endothelial cells lining the inner surface of blood vessels are an integral component of the BBB system. Sealed by tight junctions, they are crucial in maintaining homeostatic activities of the brain, as well as acting as an interface in the neurovascular unit. Additional potential vascular mechanisms such as inflammation, altered neurovascular coupling, or changes in blood flow that can modulate neuronal circuit activity have been implicated in epilepsy. Our own work has shown how intrinsic defects within endothelial cells from the earliest developmental time points, which preclude neuronal changes, can lead to vascular abnormalities and autonomously support the development of hyperexcitability and epileptiform activity. In this article, we review the importance of vascular integrity and signaling for network excitability and epilepsy by highlighting complementary basic and clinical research studies and by outlining possible novel therapeutic strategies.
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Affiliation(s)
- Jugajyoti Baruah
- Department of Psychiatry, Harvard Medical School, Boston, MA, United States.,Angiogenesis and Brain Development Laboratory, Division of Basic Neuroscience, McLean Hospital, Belmont, MA, United States
| | - Anju Vasudevan
- Department of Psychiatry, Harvard Medical School, Boston, MA, United States.,Angiogenesis and Brain Development Laboratory, Division of Basic Neuroscience, McLean Hospital, Belmont, MA, United States
| | - Rüdiger Köhling
- Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, Rostock, Germany
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30
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Schaffenrath J, Keller A. New Insights in the Complexity and Functionality of the Neurovascular Unit. Handb Exp Pharmacol 2020; 273:33-57. [PMID: 33582883 DOI: 10.1007/164_2020_424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The neurovascular unit (NVU) encompasses all brain cells and underlines that neurons, glia and brain vasculature are in intimate physical and functional association. Brain function is dependent on blood flow and local increases in blood flow in response to neural activity - functional hyperaemia takes place at the NVU. Although this is a vital function of the NVU, many studies have demonstrated that the NVU also performs other tasks. Blood vessels in the brain, which are composed of multiple cell types, are essential for correct brain development. They constitute the niche for brain stem cells, sense the environment and communicate changes to neural tissue, and control the immune quiescence of the CNS. In this brief chapter we will discuss new insights into the biology of NVU, which have further revealed the heterogeneity and complexity of the vascular tree and its neurovascular associations.
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Affiliation(s)
- Johanna Schaffenrath
- Department of Neurosurgery, Clinical Neuroscience Center, Zurich Neuroscience Center, Zurich University Hospital, Zurich University, Zurich, Switzerland
| | - Annika Keller
- Department of Neurosurgery, Clinical Neuroscience Center, Zurich Neuroscience Center, Zurich University Hospital, Zurich University, Zurich, Switzerland.
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31
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Cellular Mechanisms of Angiogenesis in Neonatal Rat Models of Retinal Neurodegeneration. Int J Mol Sci 2019; 20:ijms20194759. [PMID: 31557901 PMCID: PMC6801463 DOI: 10.3390/ijms20194759] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 09/23/2019] [Accepted: 09/23/2019] [Indexed: 11/17/2022] Open
Abstract
Νeuronal and glial cells play an important role in the development of vasculature in the retina. In this study, we investigated whether re-vascularization occurs in retinal neurodegenerative injury models. To induce retinal injury, N-methyl-D-aspartic acid (NMDA, 200 nmol) or kainic acid (KA, 20 nmol) was injected into the vitreous chamber of the eye on postnatal day (P)7. Morphological changes in retinal neurons and vasculature were assessed on P14, P21, and P35. Prevention of vascular growth and regression of some capillaries were observed on P14 in retinas of NMDA- and KA-treated eyes. However, vascular growth and re-vascularization started on P21, and the retinal vascular network was established by P35 in retinas with neurodegenerative injuries. The re-vascularization was suppressed by a two-day treatment with KRN633, an inhibitor of VEGF receptor tyrosine kinase, on P21 and P22. Astrocytes and Müller cells expressed vascular endothelial growth factor (VEGF), and the distribution pattern of VEGF was almost the same between the control and the NMDA-induced retinal neurodegenerative injury model, except for the difference in the thickness of the inner retinal layer. During re-vascularization, angiogenic sprouts from pre-existing blood vessels were present along the network of fibronectins formed by astrocytes. These results suggest that glial cells contribute to angiogenesis in neonatal rat models of retinal neurodegeneration.
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32
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Calderón-Peláez MA, Velandia-Romero ML, Bastidas-Legarda LY, Beltrán EO, Camacho-Ortega SJ, Castellanos JE. Dengue Virus Infection of Blood-Brain Barrier Cells: Consequences of Severe Disease. Front Microbiol 2019; 10:1435. [PMID: 31293558 PMCID: PMC6606788 DOI: 10.3389/fmicb.2019.01435] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 06/06/2019] [Indexed: 01/10/2023] Open
Abstract
More than 500 million people worldwide are infected each year by any of the four-dengue virus (DENV) serotypes. The clinical spectrum caused during these infections is wide and some patients may develop neurological alterations during or after the infection, which could be explained by the cryptic neurotropic and neurovirulent features of flaviviruses like DENV. Using in vivo and in vitro models, researchers have demonstrated that DENV can affect the cells from the blood-brain barrier (BBB) in several ways, which could result in brain tissue damage, neuronal loss, glial activation, tissue inflammation and hemorrhages. The latter suggests that BBB may be compromised during infection; however, it is not clear whether the damage is due to the infection per se or to the local and/or systemic inflammatory response established or activated by the BBB cells. Similarly, the kinetics and cascade of events that trigger tissue damage, and the cells that initiate it, are unknown. This review presents evidence of the BBB cell infection with DENV and the response established toward it by these cells; it also describes the consequences of this response on the nervous tissue, compares these evidence with the one reported with neurotropic viruses of the Flaviviridae family, and shows the complexity and unpredictability of dengue and the neurological alterations induced by it. Clinical evidence and in vitro and in vivo models suggest that this virus uses the bloodstream to enter nerve tissue where it infects the different cells of the neurovascular unit. Each of the cell populations respond individually and collectively and control infection and inflammation, in other cases this response exacerbates the damage leaving irreversible sequelae or causing death. This information will allow us to understand more about the complex disease known as dengue, and its impact on a specialized and delicate tissue like is the nervous tissue.
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33
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Puelles L, Martínez-Marin R, Melgarejo-Otalora P, Ayad A, Valavanis A, Ferran JL. Patterned Vascularization of Embryonic Mouse Forebrain, and Neuromeric Topology of Major Human Subarachnoidal Arterial Branches: A Prosomeric Mapping. Front Neuroanat 2019; 13:59. [PMID: 31275117 PMCID: PMC6593354 DOI: 10.3389/fnana.2019.00059] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 05/22/2019] [Indexed: 01/24/2023] Open
Abstract
The prosomeric brain model contemplates progressive regionalization of the central nervous system (CNS) from a molecular and morphological ontogenetic perspective. It defines the forebrain axis relative to the notochord, and contemplates intersecting longitudinal (zonal, columnar) and transversal (neuromeric) patterning mechanisms. A checkboard pattern of histogenetic units of the neural wall results, where each unit is differentially fated by an unique profile of active genes. These natural neural units later expand their radial dimension during neurogenesis, histogenesis, and correlative differential morphogenesis. This fundamental topologic framework is shared by all vertebrates, as a Bauplan, each lineage varying in some subtle aspects. So far the prosomeric model has been applied only to neural structures, but we attempt here a prosomeric analysis of the hypothesis that major vessels invade the brain wall in patterns that are congruent with its intrinsic natural developmental units, as postulated in the prosomeric model. Anatomic and embryologic studies of brain blood vessels have classically recorded a conserved pattern of branches (thus the conventional terminology), and clinical experience has discovered a standard topography of many brain arterial terminal fields. Such results were described under assumptions of the columnar model of the forebrain, prevalent during the last century, but this is found insufficient in depth and explanatory power in the modern molecular scenario. We have thus explored the possibility that brain vascularization in rodents and humans may relate systematically to genoarchitectonic forebrain subdivisions contemplated in the prosomeric model. Specifically, we examined first whether early vascular invasion of some molecularly characterized prosomeric domains shows heterochrony. We indeed found a heterochronic pattern of vascular invasion that distinguishes between adjacent brain areas with differential molecular profiles. We next mapped topologically on the prosomeric model the major arterial branches serving the human brain. The results of this approach bear on the possibility of a developmentally-based modern arterial terminology.
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Affiliation(s)
- Luis Puelles
- Department of Human Anatomy, School of Medicine, University of Murcia and IMIB-Arrixaca Institute, Murcia, Spain
| | - Rafael Martínez-Marin
- Department of Human Anatomy, School of Medicine, University of Murcia and IMIB-Arrixaca Institute, Murcia, Spain
| | - Pedro Melgarejo-Otalora
- Department of Human Anatomy, School of Medicine, University of Murcia and IMIB-Arrixaca Institute, Murcia, Spain
| | - Abdelmalik Ayad
- Department of Human Anatomy, School of Medicine, University of Murcia and IMIB-Arrixaca Institute, Murcia, Spain
| | - Antonios Valavanis
- Department of Neuroradiology, University Hospital of Zurich, Zurich, Switzerland
| | - José Luis Ferran
- Department of Human Anatomy, School of Medicine, University of Murcia and IMIB-Arrixaca Institute, Murcia, Spain
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34
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Quiñonez-Silvero C, Hübner K, Herzog W. Development of the brain vasculature and the blood-brain barrier in zebrafish. Dev Biol 2019; 457:181-190. [PMID: 30862465 DOI: 10.1016/j.ydbio.2019.03.005] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 03/06/2019] [Accepted: 03/08/2019] [Indexed: 12/13/2022]
Abstract
To ensure tissue homeostasis the brain needs to be protected from blood-derived fluctuations or pathogens that could affect its function. Therefore, the brain capillaries develop tissue-specific properties to form a selective blood-brain barrier (BBB), allowing the passage of essential molecules to the brain and blocking the penetration of potentially harmful compounds or cells. Previous studies reported the presence of this barrier in zebrafish. The intrinsic features of the zebrafish embryos and larvae in combination with optical techniques, make them suitable for the study of barrier establishment and maturation. In this review, we discuss the most recent contributions to the development and formation of a functional zebrafish BBB. Moreover, we compare the molecular and cellular characteristic of the zebrafish and the mammalian BBB.
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Affiliation(s)
- Claudia Quiñonez-Silvero
- University of Muenster, Muenster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Muenster, Germany
| | - Kathleen Hübner
- University of Muenster, Muenster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Muenster, Germany
| | - Wiebke Herzog
- University of Muenster, Muenster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Muenster, Germany; Max Planck Institute for Molecular Biomedicine, Muenster, Germany.
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35
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Alabi RO, Farber G, Blobel CP. Intriguing Roles for Endothelial ADAM10/Notch Signaling in the Development of Organ-Specific Vascular Beds. Physiol Rev 2019; 98:2025-2061. [PMID: 30067156 DOI: 10.1152/physrev.00029.2017] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The vasculature is a remarkably interesting, complex, and interconnected organ. It provides a conduit for oxygen and nutrients, filtration of waste products, and rapid communication between organs. Much remains to be learned about the specialized vascular beds that fulfill these diverse, yet vital functions. This review was prompted by the discovery that Notch signaling in mouse endothelial cells is crucial for the development of specialized vascular beds found in the heart, kidneys, liver, intestines, and bone. We will address the intriguing questions raised by the role of Notch signaling and that of its regulator, the metalloprotease ADAM10, in the development of specialized vascular beds. We will cover fundamentals of ADAM10/Notch signaling, the concept of Notch-dependent cell fate decisions, and how these might govern the development of organ-specific vascular beds through angiogenesis or vasculogenesis. We will also consider common features of the affected vessels, including the presence of fenestra or sinusoids and their occurrence in portal systems with two consecutive capillary beds. We hope to stimulate further discussion and study of the role of ADAM10/Notch signaling in the development of specialized vascular structures, which might help uncover new targets for the repair of vascular beds damaged in conditions like coronary artery disease and glomerulonephritis.
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Affiliation(s)
- Rolake O Alabi
- Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, New York ; Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York ; Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, New York ; Department of Medicine, Weill Cornell Medicine, New York, New York ; and Institute for Advanced Study, Technical University Munich , Munich , Germany
| | - Gregory Farber
- Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, New York ; Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York ; Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, New York ; Department of Medicine, Weill Cornell Medicine, New York, New York ; and Institute for Advanced Study, Technical University Munich , Munich , Germany
| | - Carl P Blobel
- Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, New York ; Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York ; Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, New York ; Department of Medicine, Weill Cornell Medicine, New York, New York ; and Institute for Advanced Study, Technical University Munich , Munich , Germany
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36
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Parfenov VA, Ostroumova OD, Ostroumova TM, Kochetkov AI, Fateeva VV, Khacheva KK, Khakimova GR, Epstein OI. Vascular cognitive impairment: pathophysiological mechanisms, insights into structural basis, and perspectives in specific treatments. Neuropsychiatr Dis Treat 2019; 15:1381-1402. [PMID: 31190841 PMCID: PMC6535085 DOI: 10.2147/ndt.s197032] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 02/14/2019] [Indexed: 01/19/2023] Open
Abstract
Vascular cognitive impairment (VCI) and vascular dementia are the most common forms of cognitive disorder associated with cerebrovascular disease and related to increased morbidity and mortality among the older population. Growing evidence suggests the contribution of blood-pressure variability, cardiac arrhythmia, hyperactivation of the renin-angiotensin-aldosterone system, endothelial dysfunction, vascular remodeling and stiffness, different angiopathies, neural tissue homeostasis, and systemic metabolic disorders to the pathophysiology of VCI. In this review, we focus on factors contributing to cerebrovascular disease, neurovascular unit alterations, and novel approaches to cognitive improvement in patients with cognitive decline. One of the important factors associated with the neuronal causes of VCI is the S100B protein, which can affect the expression of cytokines in the brain, support homeostasis, and regulate processes of differentiation, repair, and apoptosis of the nervous tissue. Since the pathological basis of VCI is complex and diverse, treatment affecting the mechanisms of cognitive disorders should be developed. The prospective role of a novel complex drug consisting of released-active antibodies to S100 and to endothelial NO synthase in VCI treatment is highlighted.
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Affiliation(s)
- Vladimir A Parfenov
- Department of Neurology, Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation
| | - Olga D Ostroumova
- Laboratory of Clinical Pharmacology and therapy, Federal State Budgetary Educational Institution of Higher Education "N.I. Pirogov Russian National Research Medical University" of the Ministry of Health of the Russian Federation, Russian Clinical and Research Center of Gerontology, Moscow, Russia.,Department of Clinical Pharmacology, Internal Medicine and Propaedeutics I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Tatiana M Ostroumova
- Department of Neurology, Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation
| | - Alexey I Kochetkov
- Laboratory of Clinical Pharmacology and therapy, Federal State Budgetary Educational Institution of Higher Education "N.I. Pirogov Russian National Research Medical University" of the Ministry of Health of the Russian Federation, Russian Clinical and Research Center of Gerontology, Moscow, Russia
| | - Victoria V Fateeva
- Medical Information Department, OOO NPF Materia Medica Holding, Moscow, Russian Federation
| | - Kristina K Khacheva
- Medical Information Department, OOO NPF Materia Medica Holding, Moscow, Russian Federation
| | - Gulnara R Khakimova
- Research and Analytical Division of Scientific Research and Development Department, Moscow, Russian Federation
| | - Oleg I Epstein
- Laboratory of Physiologicaly Active Substances, Department of Molecular and Cellular Pathophysiology, Research Institute of General Pathology and Pathophysiology, Moscow, Russian Federation
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Hübner K, Cabochette P, Diéguez-Hurtado R, Wiesner C, Wakayama Y, Grassme KS, Hubert M, Guenther S, Belting HG, Affolter M, Adams RH, Vanhollebeke B, Herzog W. Wnt/β-catenin signaling regulates VE-cadherin-mediated anastomosis of brain capillaries by counteracting S1pr1 signaling. Nat Commun 2018; 9:4860. [PMID: 30451830 PMCID: PMC6242933 DOI: 10.1038/s41467-018-07302-x] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 10/15/2018] [Indexed: 02/08/2023] Open
Abstract
Canonical Wnt signaling is crucial for vascularization of the central nervous system and blood-brain barrier (BBB) formation. BBB formation and modulation are not only important for development, but also relevant for vascular and neurodegenerative diseases. However, there is little understanding of how Wnt signaling contributes to brain angiogenesis and BBB formation. Here we show, using high resolution in vivo imaging and temporal and spatial manipulation of Wnt signaling, different requirements for Wnt signaling during brain angiogenesis and BBB formation. In the absence of Wnt signaling, premature Sphingosine-1-phosphate receptor (S1pr) signaling reduces VE-cadherin and Esama at cell-cell junctions. We suggest that Wnt signaling suppresses S1pr signaling during angiogenesis to enable the dynamic junction formation during anastomosis, whereas later S1pr signaling regulates BBB maturation and VE-cadherin stabilization. Our data provides a link between brain angiogenesis and BBB formation and identifies Wnt signaling as coordinator of the timing and as regulator of anastomosis.
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Affiliation(s)
- Kathleen Hübner
- University of Muenster, Schlossplatz 2, 48149, Muenster, Germany
- Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Muenster, Waldeyerstrasse 15, 48149, Muenster, Germany
| | - Pauline Cabochette
- Université libre de Bruxelles, Rue Prof. Jeener et Brachet 12, 6041, Gosselies, Belgium
| | - Rodrigo Diéguez-Hurtado
- Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Muenster, Waldeyerstrasse 15, 48149, Muenster, Germany
- Max Planck Institute for Molecular Biomedicine, Roentgenstrasse 20, 48149, Muenster, Germany
| | - Cora Wiesner
- Biozentrum der Universität Basel, Klingelbergstrasse 70, 4056, Basel, Switzerland
| | - Yuki Wakayama
- University of Muenster, Schlossplatz 2, 48149, Muenster, Germany
| | | | - Marvin Hubert
- University of Muenster, Schlossplatz 2, 48149, Muenster, Germany
| | - Stefan Guenther
- Max Planck Institute for Heart and Lung Research, ECCPS Bioinformatics and Deep Sequencing Platform, Ludwigstrasse 43, 61231, Bad Nauheim, Germany
| | - Heinz-Georg Belting
- Biozentrum der Universität Basel, Klingelbergstrasse 70, 4056, Basel, Switzerland
| | - Markus Affolter
- Biozentrum der Universität Basel, Klingelbergstrasse 70, 4056, Basel, Switzerland
| | - Ralf H Adams
- Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Muenster, Waldeyerstrasse 15, 48149, Muenster, Germany
- Max Planck Institute for Molecular Biomedicine, Roentgenstrasse 20, 48149, Muenster, Germany
| | - Benoit Vanhollebeke
- Université libre de Bruxelles, Rue Prof. Jeener et Brachet 12, 6041, Gosselies, Belgium
- Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Avenue Pasteur 6, 1300, Wavre, Belgium
| | - Wiebke Herzog
- University of Muenster, Schlossplatz 2, 48149, Muenster, Germany.
- Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Muenster, Waldeyerstrasse 15, 48149, Muenster, Germany.
- Max Planck Institute for Molecular Biomedicine, Roentgenstrasse 20, 48149, Muenster, Germany.
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38
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Affiliation(s)
- Jean-Leon Thomas
- Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, USA. .,Université Pierre et Marie Curie Paris 06 UMRS1127, Sorbonne Université, Institut du Cerveau et de la Moelle Epinière, Paris, France
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39
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Ramesh S, Govindarajulu M, Suppiramaniam V, Moore T, Dhanasekaran M. Autotaxin⁻Lysophosphatidic Acid Signaling in Alzheimer's Disease. Int J Mol Sci 2018; 19:ijms19071827. [PMID: 29933579 PMCID: PMC6073975 DOI: 10.3390/ijms19071827] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 06/12/2018] [Accepted: 06/18/2018] [Indexed: 12/14/2022] Open
Abstract
The brain contains various forms of lipids that are important for maintaining its structural integrity and regulating various signaling cascades. Autotaxin (ATX) is an ecto-nucleotide pyrophosphatase/phosphodiesterase-2 enzyme that hydrolyzes extracellular lysophospholipids into the lipid mediator lysophosphatidic acid (LPA). LPA is a major bioactive lipid which acts through G protein-coupled receptors (GPCRs) and plays an important role in mediating cellular signaling processes. The majority of synthesized LPA is derived from membrane phospholipids through the action of the secreted enzyme ATX. Both ATX and LPA are highly expressed in the central nervous system. Dysfunctional expression and activity of ATX with associated changes in LPA signaling have recently been implicated in the pathogenesis of Alzheimer’s disease (AD). This review focuses on the current understanding of LPA signaling, with emphasis on the importance of the autotaxin–lysophosphatidic acid (ATX–LPA) pathway and its alterations in AD and a brief note on future therapeutic applications based on ATX–LPA signaling.
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Affiliation(s)
- Sindhu Ramesh
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
| | - Manoj Govindarajulu
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
| | - Vishnu Suppiramaniam
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
| | - Timothy Moore
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
| | - Muralikrishnan Dhanasekaran
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
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Paredes I, Himmels P, Ruiz de Almodóvar C. Neurovascular Communication during CNS Development. Dev Cell 2018; 45:10-32. [PMID: 29634931 DOI: 10.1016/j.devcel.2018.01.023] [Citation(s) in RCA: 151] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 11/22/2017] [Accepted: 01/08/2018] [Indexed: 12/11/2022]
Abstract
A precise communication between the nervous and the vascular systems is crucial for proper formation and function of the central nervous system (CNS). Interestingly, this communication does not only occur by neural cells regulating the growth and properties of the vasculature, but new studies show that blood vessels actively control different neurodevelopmental processes. Here, we review the current knowledge on how neurons in particular influence growing blood vessels during CNS development and on how vessels participate in shaping the neural compartment. We also review the identified molecular mechanisms of this bidirectional communication.
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Affiliation(s)
- Isidora Paredes
- Biochemistry Center, Heidelberg University, 69120 Heidelberg, Germany; Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Patricia Himmels
- Biochemistry Center, Heidelberg University, 69120 Heidelberg, Germany; Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Carmen Ruiz de Almodóvar
- Biochemistry Center, Heidelberg University, 69120 Heidelberg, Germany; Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany.
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41
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Monti L, Morbidelli L, Rossi A. Impaired Cerebral Perfusion in Multiple Sclerosis: Relevance of Endothelial Factors. Biomark Insights 2018; 13:1177271918774800. [PMID: 29795976 PMCID: PMC5960845 DOI: 10.1177/1177271918774800] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 04/07/2018] [Indexed: 12/21/2022] Open
Abstract
Magnetic resonance imaging techniques measuring in vivo brain perfusion and integrity of the blood-brain barrier have developed rapidly in the past decade, resulting in a wide range of available methods. This review first discusses their principles, possible pitfalls, and potential for quantification and outlines clinical application in neurological disorders. Then, we focus on the endothelial cells of the blood-brain barrier, pointing out their contribution in regulating vascular tone by production of vasoactive substances. Finally, the role of these substances in brain hypoperfusion in multiple sclerosis is discussed.
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Affiliation(s)
- Lucia Monti
- Unit of Neuroimaging and Neurointervention, Department of Neurological and Neurosensory Sciences, "Santa Maria alle Scotte" General Hospital, University Hospital of Siena, Siena, Italy
| | | | - Alessandro Rossi
- Unit of Neurology and Clinical Neurophysiology, Department of Neurological and Neurosensory Sciences, University Hospital of Siena, Siena, Italy
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42
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Madelaine R, Sloan SA, Huber N, Notwell JH, Leung LC, Skariah G, Halluin C, Paşca SP, Bejerano G, Krasnow MA, Barres BA, Mourrain P. MicroRNA-9 Couples Brain Neurogenesis and Angiogenesis. Cell Rep 2018; 20:1533-1542. [PMID: 28813666 DOI: 10.1016/j.celrep.2017.07.051] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 06/30/2017] [Accepted: 07/19/2017] [Indexed: 12/22/2022] Open
Abstract
In the developing brain, neurons expressing VEGF-A and blood vessels grow in close apposition, but many of the molecular pathways regulating neuronal VEGF-A and neurovascular system development remain to be deciphered. Here, we show that miR-9 links neurogenesis and angiogenesis through the formation of neurons expressing VEGF-A. We found that miR-9 directly targets the transcription factors TLX and ONECUTs to regulate VEGF-A expression. miR-9 inhibition leads to increased TLX and ONECUT expression, resulting in VEGF-A overexpression. This untimely increase of neuronal VEGF-A signal leads to the thickening of blood vessels at the expense of the normal formation of the neurovascular network in the brain and retina. Thus, this conserved transcriptional cascade is critical for proper brain development in vertebrates. Because of this dual role on neural stem cell proliferation and angiogenesis, miR-9 and its downstream targets are promising factors for cellular regenerative therapy following stroke and for brain tumor treatment.
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Affiliation(s)
- Romain Madelaine
- Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Steven A Sloan
- Department of Neurobiology, Stanford University, Stanford, CA 94305, USA
| | - Nina Huber
- Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - James H Notwell
- Department of Computer Science, Stanford University, Stanford, CA 94305, USA
| | - Louis C Leung
- Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Gemini Skariah
- Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Caroline Halluin
- Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Sergiu P Paşca
- Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
| | - Gill Bejerano
- Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA
| | - Mark A Krasnow
- HHMI and Department of Biochemistry, Stanford University, Stanford, CA 94305, USA
| | - Ben A Barres
- Department of Neurobiology, Stanford University, Stanford, CA 94305, USA
| | - Philippe Mourrain
- Stanford Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; INSERM 1024, École Normale Supérieure, Paris 75005, France.
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43
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Cross-talk between blood vessels and neural progenitors in the developing brain. Neuronal Signal 2018; 2:NS20170139. [PMID: 32714582 PMCID: PMC7371013 DOI: 10.1042/ns20170139] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 02/20/2018] [Accepted: 02/21/2018] [Indexed: 01/26/2023] Open
Abstract
The formation of the central nervous system (CNS) involves multiple cellular and molecular interactions between neural progenitor cells (NPCs) and blood vessels to establish extensive and complex neural networks and attract a vascular supply that support their function. In this review, we discuss studies that have performed genetic manipulations of chick, fish and mouse embryos to define the spatiotemporal roles of molecules that mediate the reciprocal regulation of NPCs and blood vessels. These experiments have highlighted core functions of NPC-expressed ligands in initiating vascular growth into and within the neural tube as well as establishing the blood-brain barrier. More recent findings have also revealed indispensable roles of blood vessels in regulating NPC expansion and eventual differentiation, and specific regional differences in the effect of angiocrine signals. Accordingly, NPCs initially stimulate blood vessel growth and maturation to nourish the brain, but blood vessels subsequently also regulate NPC behaviour to promote the formation of a sufficient number and diversity of neural cells. A greater understanding of the molecular cross-talk between NPCs and blood vessels will improve our knowledge of how the vertebrate nervous system forms and likely help in the design of novel therapies aimed at regenerating neurons and neural vasculature following CNS disease or injury.
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44
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Joyal JS, Gantner ML, Smith LEH. Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism. Prog Retin Eye Res 2017; 64:131-156. [PMID: 29175509 DOI: 10.1016/j.preteyeres.2017.11.002] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 11/11/2017] [Accepted: 11/15/2017] [Indexed: 12/15/2022]
Affiliation(s)
- Jean-Sébastien Joyal
- Department of Pediatrics, Pharmacology and Ophthalmology, CHU Sainte-Justine Research Center, Université de Montréal, Montreal, Qc, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Qc, Canada.
| | - Marin L Gantner
- The Lowy Medical Research Institute, La Jolla, United States
| | - Lois E H Smith
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston MA 02115, United States.
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45
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Wang H, Hartnett ME. Roles of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase in Angiogenesis: Isoform-Specific Effects. Antioxidants (Basel) 2017; 6:antiox6020040. [PMID: 28587189 PMCID: PMC5488020 DOI: 10.3390/antiox6020040] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 05/24/2017] [Accepted: 05/31/2017] [Indexed: 12/19/2022] Open
Abstract
Angiogenesis is the formation of new blood vessels from preexisting ones and is implicated in physiologic vascular development, pathologic blood vessel growth, and vascular restoration. This is in contrast to vasculogenesis, which is de novo growth of vessels from vascular precursors, or from vascular repair that occurs when circulating endothelial progenitor cells home into an area and develop into blood vessels. The objective of this review is to discuss the isoform-specific role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in physiologic and pathologic angiogenesis and vascular repair, but will not specifically address vasculogenesis. As the major source of reactive oxygen species (ROS) in vascular endothelial cells (ECs), NOX has gained increasing attention in angiogenesis. Activation of NOX leads to events necessary for physiologic and pathologic angiogenesis, including EC migration, proliferation and tube formation. However, activation of different NOX isoforms has different effects in angiogenesis. Activation of NOX2 promotes pathologic angiogenesis and vascular inflammation, but may be beneficial in revascularization in the hindlimb ischemic model. In contrast, activation of NOX4 appears to promote physiologic angiogenesis mainly by protecting the vasculature during ischemia, hypoxia and inflammation and by restoring vascularization, except in models of oxygen-induced retinopathy and diabetes where NOX4 activation leads to pathologic angiogenesis.
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Affiliation(s)
- Haibo Wang
- The John A. Moran Eye Center, University of Utah, 65 N. Mario Capecchi Drive, Salt Lake City, UT 84132, USA.
| | - M Elizabeth Hartnett
- The John A. Moran Eye Center, University of Utah, 65 N. Mario Capecchi Drive, Salt Lake City, UT 84132, USA.
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46
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McConnell HL, Kersch CN, Woltjer RL, Neuwelt EA. The Translational Significance of the Neurovascular Unit. J Biol Chem 2016; 292:762-770. [PMID: 27920202 DOI: 10.1074/jbc.r116.760215] [Citation(s) in RCA: 210] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The mammalian brain is supplied with blood by specialized vasculature that is structurally and functionally distinct from that of the periphery. A defining feature of this vasculature is a physical blood-brain barrier (BBB). The BBB separates blood components from the brain microenvironment, regulating the entry and exit of ions, nutrients, macromolecules, and energy metabolites. Over the last two decades, physiological studies of cerebral blood flow dynamics have demonstrated that substantial intercellular communication occurs between cells of the vasculature and the neurons and glia that abut the vasculature. These findings suggest that the BBB does not function independently, but as a module within the greater context of a multicellular neurovascular unit (NVU) that includes neurons, astrocytes, pericytes, and microglia as well as the blood vessels themselves. Here, we describe the roles of these NVU components as well as how they act in concert to modify cerebrovascular function and permeability in health and in select diseases.
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Affiliation(s)
- Heather L McConnell
- From the Departments of Neurology, Pathology, Neurosurgery, and Veterans Affairs, Oregon Health & Science University, Portland, Oregon 97239-2941
| | - Cymon N Kersch
- From the Departments of Neurology, Pathology, Neurosurgery, and Veterans Affairs, Oregon Health & Science University, Portland, Oregon 97239-2941
| | - Randall L Woltjer
- From the Departments of Neurology, Pathology, Neurosurgery, and Veterans Affairs, Oregon Health & Science University, Portland, Oregon 97239-2941
| | - Edward A Neuwelt
- From the Departments of Neurology, Pathology, Neurosurgery, and Veterans Affairs, Oregon Health & Science University, Portland, Oregon 97239-2941
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47
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Liu LYM, Lin MH, Lai ZY, Jiang JP, Huang YC, Jao LE, Chuang YJ. Motor neuron-derived Thsd7a is essential for zebrafish vascular development via the Notch-dll4 signaling pathway. J Biomed Sci 2016; 23:59. [PMID: 27484901 PMCID: PMC4971630 DOI: 10.1186/s12929-016-0277-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 07/18/2016] [Indexed: 11/10/2022] Open
Abstract
Background Development of neural and vascular systems displays astonishing similarities among vertebrates. This parallelism is under a precise control of complex guidance signals and neurovascular interactions. Previously, our group identified a highly conserved neural protein called thrombospondin type I domain containing 7A (THSD7A). Soluble THSD7A promoted and guided endothelial cell migration, tube formation and sprouting. In addition, we showed that thsd7a could be detected in the nervous system and was required for intersegmental vessels (ISV) patterning during zebrafish development. However, the exact origin of THSD7A and its effect on neurovascular interaction remains unclear. Results In this study, we discovered that zebrafish thsd7a was expressed in the primary motor neurons. Knockdown of Thsd7a disrupted normal primary motor neuron formation and ISV sprouting in the Tg(kdr:EGFP/mnx1:TagRFP) double transgenic zebrafish. Interestingly, we found that Thsd7a morphants displayed distinct phenotypes that are very similar to the loss of Notch-delta like 4 (dll4) signaling. Transcript profiling further revealed that expression levels of notch1b and its downstream targets, vegfr2/3 and nrarpb, were down-regulated in the Thsd7a morphants. These data supported that zebrafish Thsd7a could regulate angiogenic sprouting via Notch-dll4 signaling during development. Conclusions Our results suggested that motor neuron-derived Thsd7a plays a significant role in neurovascular interactions. Thsd7a could regulate ISV angiogenesis via Notch-dll4 signaling. Thus, Thsd7a is a potent angioneurin involved in the development of both neural and vascular systems. Electronic supplementary material The online version of this article (doi:10.1186/s12929-016-0277-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lawrence Yu-Min Liu
- Department of Medical Science & Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan.,Division of Cardiology, Department of Internal Medicine, Mackay Memorial Hospital Hsinchu Branch, Hsinchu, 30071, Taiwan
| | - Min-Hsuan Lin
- Department of Medical Science & Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Zih-Yin Lai
- Department of Medical Science & Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Jie-Peng Jiang
- Department of Medical Science & Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Yi-Ching Huang
- Department of Medical Science & Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Li-En Jao
- Department of Cell Biology and Human Anatomy, UC Davis School of Medicine, 4415 Tupper Hall, One Shields Avenue, Davis, CA, 95616, USA
| | - Yung-Jen Chuang
- Department of Medical Science & Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan.
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Intracellular Calcium Dysregulation: Implications for Alzheimer's Disease. BIOMED RESEARCH INTERNATIONAL 2016; 2016:6701324. [PMID: 27340665 PMCID: PMC4909906 DOI: 10.1155/2016/6701324] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 05/15/2016] [Indexed: 12/31/2022]
Abstract
Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive neuronal loss. AD is associated with aberrant processing of the amyloid precursor protein, which leads to the deposition of amyloid-β plaques within the brain. Together with plaques deposition, the hyperphosphorylation of the microtubules associated protein tau and the formation of intraneuronal neurofibrillary tangles are a typical neuropathological feature in AD brains. Cellular dysfunctions involving specific subcellular compartments, such as mitochondria and endoplasmic reticulum (ER), are emerging as crucial players in the pathogenesis of AD, as well as increased oxidative stress and dysregulation of calcium homeostasis. Specifically, dysregulation of intracellular calcium homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Aberrant calcium signaling has been considered a phenomenon mainly related to the dysfunction of intracellular calcium stores, which can occur in both neuronal and nonneuronal cells. This review reports the most recent findings on cellular mechanisms involved in the pathogenesis of AD, with main focus on the control of calcium homeostasis at both cytosolic and mitochondrial level.
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Raimondi C, Brash JT, Fantin A, Ruhrberg C. NRP1 function and targeting in neurovascular development and eye disease. Prog Retin Eye Res 2016; 52:64-83. [PMID: 26923176 PMCID: PMC4854174 DOI: 10.1016/j.preteyeres.2016.02.003] [Citation(s) in RCA: 61] [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: 12/23/2015] [Revised: 02/08/2016] [Accepted: 02/10/2016] [Indexed: 12/19/2022]
Abstract
Neuropilin 1 (NRP1) is expressed by neurons, blood vessels, immune cells and many other cell types in the mammalian body and binds a range of structurally and functionally diverse extracellular ligands to modulate organ development and function. In recent years, several types of mouse knockout models have been developed that have provided useful tools for experimental investigation of NRP1 function, and a multitude of therapeutics targeting NRP1 have been designed, mostly with the view to explore them for cancer treatment. This review provides a general overview of current knowledge of the signalling pathways that are modulated by NRP1, with particular focus on neuronal and vascular roles in the brain and retina. This review will also discuss the potential of NRP1 inhibitors for the treatment for neovascular eye diseases.
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Affiliation(s)
- Claudio Raimondi
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK
| | - James T Brash
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK
| | - Alessandro Fantin
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK
| | - Christiana Ruhrberg
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
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Ulrich F, Carretero-Ortega J, Menéndez J, Narvaez C, Sun B, Lancaster E, Pershad V, Trzaska S, Véliz E, Kamei M, Prendergast A, Kidd KR, Shaw KM, Castranova DA, Pham VN, Lo BD, Martin BL, Raible DW, Weinstein BM, Torres-Vázquez J. Reck enables cerebrovascular development by promoting canonical Wnt signaling. Development 2015; 143:147-59. [PMID: 26657775 DOI: 10.1242/dev.123059] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 11/25/2015] [Indexed: 01/03/2023]
Abstract
The cerebral vasculature provides the massive blood supply that the brain needs to grow and survive. By acquiring distinctive cellular and molecular characteristics it becomes the blood-brain barrier (BBB), a selectively permeable and protective interface between the brain and the peripheral circulation that maintains the extracellular milieu permissive for neuronal activity. Accordingly, there is great interest in uncovering the mechanisms that modulate the formation and differentiation of the brain vasculature. By performing a forward genetic screen in zebrafish we isolated no food for thought (nft (y72)), a recessive late-lethal mutant that lacks most of the intracerebral central arteries (CtAs), but not other brain blood vessels. We found that the cerebral vascularization deficit of nft (y72) mutants is caused by an inactivating lesion in reversion-inducing cysteine-rich protein with Kazal motifs [reck; also known as suppressor of tumorigenicity 15 protein (ST15)], which encodes a membrane-anchored tumor suppressor glycoprotein. Our findings highlight Reck as a novel and pivotal modulator of the canonical Wnt signaling pathway that acts in endothelial cells to enable intracerebral vascularization and proper expression of molecular markers associated with BBB formation. Additional studies with cultured endothelial cells suggest that, in other contexts, Reck impacts vascular biology via the vascular endothelial growth factor (VEGF) cascade. Together, our findings have broad implications for both vascular and cancer biology.
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Affiliation(s)
- Florian Ulrich
- Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA
| | - Jorge Carretero-Ortega
- Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA
| | - Javier Menéndez
- Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA
| | - Carlos Narvaez
- Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA
| | - Belinda Sun
- Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA
| | - Eva Lancaster
- Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA
| | - Valerie Pershad
- Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA
| | - Sean Trzaska
- Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA
| | - Evelyn Véliz
- Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA
| | - Makoto Kamei
- Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Andrew Prendergast
- Department of Biological Structure, University of Washington, Seattle, WA 98195, USA
| | - Kameha R Kidd
- Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Kenna M Shaw
- Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Daniel A Castranova
- Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Van N Pham
- Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Brigid D Lo
- Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | | | - David W Raible
- Department of Biological Structure, University of Washington, Seattle, WA 98195, USA
| | - Brant M Weinstein
- Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jesús Torres-Vázquez
- Dept of Cell Biology, Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, 540 First Avenue, New York, NY 10016, USA
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