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: 10198032
• 负责人: John Christopher Chappell
• 金额: $ 38.95万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198032
• 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. !

项目摘要/摘要（描述） 血管将营养和氧气输送到全身，以维持每个组织的健康 器官。因此，许多临床疾病都是由血管系统引起或直接影响血管系统。提高洞察力 血管生长和维持将指导治疗策略的制定，以治疗衰弱和 通常与血管异常相关的危及生命的疾病。周细胞是血管周围的细胞 包裹并投资生长中的血管，为血管稳定性和成熟度提供必要的调节 和静止。许多病症，例如新生儿颅内出血、糖尿病视网膜病变、 血管功能和屏障破坏会加剧阿尔茨海默病和转移性癌症 特别是由于周细胞-内皮细胞相互作用的缺陷而导致的功能障碍。尽管很重要 周细胞-内皮相互作用在人类健康和疾病中的作用，关于周细胞-内皮相互作用的知识存在重大差距 周细胞被招募到并保留在特定位置（即投资）的机制 血管。我们和其他人之前已经证明，血管内皮生长因子-A (VEGF-A) 途径，通过其负受体 Flt-1（VEGF 受体-1）之一 – 特别是可溶性 Flt-1 (sFlt-1) – 产生内皮细胞表型的空间异质性，以促进有效的血管形成 （即“尖端”细胞发芽并形成新的血管分支，“茎”细胞增殖并促进血管形成） 伸长）。确切地说，这种内皮表型异质性如何有助于建立这些特定的 周细胞投资的部位尚不明确。此外，血管基底膜（vBM）介导 血管形成过程中周细胞-内皮细胞的相互作用，但尚不清楚 vBM 成分如何 III 型和 IV 型胶原蛋白（分别为 Col-III 和 Col-IV）调节下游的周细胞投资 VEGF-A 信号传导。本研究的总体目标是研究 Col-III 和 Col-IV 沉积如何 周细胞和内皮细胞之间的相互作用受到内皮细胞中 VEGF-A 信号传导的调节，但不受 周细胞，以及 (ii) 维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分析相结合来提出假设 扩展我们初步观察结果的方法表明，当 VEGF-A 信号传导被破坏时，周细胞 沿生长血管的迁移和投资减少，这种减少与异常 Col-III 和 Col-IV 的沉积，这似乎是周细胞粘附的不允许的基质 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 这对于彻底研究周细胞进入血管壁的情况至关重要。 结合这些创新方法，我们将加深对周细胞内皮细胞机制的理解 细胞相互作用并激发人类疾病新药的开发。 ！