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

• 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
• 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' 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

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. !

项目总结/摘要（描述） 血管将营养物质和氧气输送到全身，以维持每个组织的健康， 器官.因此，许多临床疾病是由血管系统引起的或直接影响血管系统。更深入地了解 血管生长和维持将指导治疗策略的发展， 通常是与血管异常有关的危及生命的疾病。周细胞是血管周围细胞， 包裹并投资于正在生长的血管，提供对血管稳定性、成熟度 和安静许多病理，如新生儿颅内出血，糖尿病视网膜病变， 阿尔茨海默氏病和转移性癌症会因血管功能和屏障功能的破坏而恶化。 特别是，由于周细胞-内皮细胞相互作用的缺陷。尽管重要的是 周细胞-内皮细胞相互作用在人类健康和疾病中的作用， 周细胞被招募并保留在特定位置（即投资）的机制 血管我们和其他人先前已经表明，血管内皮生长因子-A（VEGF-A） 途径，通过其负性受体之一Flt-1（VEGF受体-1）-可溶性Flt-1（sFlt-1）- 在内皮细胞表型中产生空间异质性以促进有效的血管形成 (i.e.“尖”细胞萌发形成新的血管分支，“柄”细胞增殖形成新的血管分支， 伸长）。确切地说，这种内皮细胞表型异质性如何有助于建立这些特异性的 周细胞包埋的位点没有很好的定义。此外，血管基底膜（vBM）介导 血管形成期间周细胞-内皮细胞相互作用，但尚不清楚vBM如何组成 III型和IV型胶原蛋白（分别为Col-III和Col-IV）调节外周细胞的下游投资， VEGF-A信号传导。本研究的总体目标是研究Col-III和Col-IV沉积 （i）在内皮细胞中受VEGF-A信号转导调节，但在内皮细胞中不受VEGF-A信号转导调节， 周细胞，和（ii）保持在精确的水平，以促进和维持周细胞投资。我们将测试这个 通过将创新的体外、离体和体内模型与尖端的分析方法相结合， 方法来扩展我们的初步观察表明，当VEGF-A信号被破坏，周细胞， 沿着沿着生长的船只的迁移和投资减少，这种减少与异常的 Col-III和Col-IV的沉积，其似乎是周细胞粘附的非允许底物， 迁移合作者将提供细胞外基质（ECM）生物学和新型成像方面的专业知识 这些方法对于彻底研究周细胞进入血管壁至关重要。 结合这些创新的方法，我们将加深我们对周细胞-内皮细胞 细胞相互作用，并启发开发用于人类疾病的新药。 !