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Vascular Basement Membrane Composition Regulates Pericyte Investment in Developing Blood Vessels

血管基底膜成分调节周细胞在血管发育中的投资

基本信息

批准号：
10449094
负责人：
John Christopher Chappell
金额：
$ 38.91万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449094
关键词：
Adhesions Affect Alzheimer&apos s Disease Antibodies Back Basement membrane Biology Blood Vessels Blood capillaries CSPG4 gene Cell Communication Cell Culture Techniques Cells Clinical Collagen Collagen Type IV DNA Sequence Alteration Data Defect Deposition Development Diabetic Retinopathy Disease Disseminated Malignant Neoplasm Drops Drug usage DsRed Elements Embryo Endothelial Cells Endothelial Growth Factors Endothelium Extracellular Matrix Genes Genetic Growth Growth Factor Health Heterogeneity Homeostasis Human Human Genetics In Vitro Intracranial Hemorrhages Investigation Investments KDR gene Knowledge LacZ Genes Lead Life Ligands Link Location Maintenance Mediating Microcirculation Modeling Mosaicism Mus Neonatal Nutrient Oranges Organ Oxygen Pathology Pathway interactions Patients Pericytes Phase Phenotype Process Production Proliferating Regulation Reporter Research Retina Role Signal Transduction Site Skin Testing Tissues VEGFA gene Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vascular System Viola blood vessel development cell type combinatorial density embryonic stem cell human disease imaging approach improved in vivo in vivo Model innovation insight migration novel novel therapeutics postnatal public health relevance receptor receptor expression recruit response therapeutic development

项目摘要

PROJECT SUMMARY / ABSTRACT (DESCRIPTION) Blood vessels deliver nutrients and oxygen throughout the body to sustain the health of every tissue and organ. Many clinical diseases therefore arise from or directly affect the vascular system. Improved insight into vessel growth and maintenance will guide the development of therapeutic strategies to treat debilitating and often life-threatening illnesses associated with blood vessel abnormalities. Pericytes are perivascular cells that wrap around and invest into growing blood vessels, providing essential regulation of vessel stability, maturity and quiescence. Numerous pathologies such as neonatal intracranial hemorrhage, diabetic retinopathy, Alzheimer's disease, and metastatic cancer are exacerbated by disrupted vascular function, and barrier function in particular, resulting from defects in pericyte-endothelial cell interactions. Despite the importance of pericyte-endothelial interactions in human health and disease, critical gaps in knowledge exist about the mechanism by which pericytes are recruited to and retained at specific locations (i.e. invest) on developing blood vessels. We and others have previously shown that the Vascular Endothelial Growth Factor-A (VEGF-A) pathway, via one of its negative receptors Flt-1 (VEGF Receptor-1) – soluble Flt-1 (sFlt-1) in particular – generates a spatial heterogeneity in endothelial cell phenotypes to promote efficient blood vessel formation (i.e. “tip” cells sprout and form new vessel branches, “stalk” cells proliferate and contribute to vessel elongation). Precisely how this endothelial phenotypic heterogeneity contributes to establishing these specific sites for pericyte investment is not well defined. Moreover, the vascular basement membrane (vBM) mediates pericyte-endothelial cell interactions during blood vessel formation, but it is not clear how the vBM components Types III and IV Collagen (Col-III and Col-IV, respectively) modulate pericyte investment downstream of VEGF-A signaling. The overall objective of this research is to investigate how Col-III and Col-IV deposition between pericytes and endothelial cells is (i) regulated by VEGF-A signaling in endothelial cells but not pericytes, and (ii) maintained at precise levels to promote and sustain pericyte investment. We will test this hypothesis by combining innovative in vitro, ex vivo, and in vivo models with cutting-edge analytical approaches to extend our preliminary observations showing that, when VEGF-A signaling is disrupted, pericyte migration and investment along growing vessels decreases, and this decrease is associated with aberrant deposition of Col-III and Col-IV, which appears to be a non-permissive substrate for pericyte adhesion and migration. Collaborators will provide expertise in extracellular matrix (ECM) biology and in novel imaging approaches that will be essential for thorough investigation of pericyte investment into the blood vessel wall. Combining these innovative approaches, we will deepen our mechanistic understanding of pericyte-endothelial cell interactions and inspire development of novel drugs for human diseases. !

项目摘要/摘要（描述）