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：
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
项目类别：
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&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）血管在整个人体中输送营养和氧气，以维持每个组织的健康和器官。因此，许多临床疾病来自或直接影响血管系统。改善了洞察力船只的增长和维护将指导理论策略的发展，以治疗衰弱和经常与血管异常有关的威胁生命的疾病。周细胞是血管周细胞缠绕并投资于增长的血管，提供对船舶稳定性，成熟度的基本调节和静止。许多病理，例如新生儿颅内出血，糖尿病性视网膜病，阿尔茨海默氏病和转移性癌症因血管功能干扰而加剧尤其是由于周周内皮细胞相互作用缺陷而产生的功能。尽管很重要人类健康和疾病中的周细胞内皮相互作用，知识中存在关键的差距招募周细胞的机制，并保留在特定地点（即投资）开发的机制血管。我们和其他人以前已经表明，血管内皮生长因子-A（VEGF-A）途径是通过其负受体FLT-1（VEGF受体1）之一 - 尤其是可溶性FLT-1（SFLT-1）的途径 - 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（即“尖端”细胞发芽并形成新的容器分支，“茎”细胞增殖并有助于血管伸长）。确切地说，这种内皮表型异质性如何有助于建立这些特定周围投资的网站没有很好地定义。此外，血管基底膜（VBM）培养基血管形成过程中周细胞 - 内皮细胞相互作用，但尚不清楚VBM成分如何 III类和IV型胶原蛋白（分别为Col-III和Col-IV）调节下游的周围投资 VEGF-A信号传导。这项研究的总体目的是研究Col-III和Col-IV沉积周细胞和内皮细胞之间是（i）由内皮细胞中的VEGF-A信号调节，但不是周细胞和（ii）保持精确水平，以促进和维持周细胞投资。我们将测试这个通过在体外，离体和体内模型与尖端分析的体外，离体和体内模型相结合来假设扩展我们的初步观察的方法，表明当VEGF-A信号被破坏时，周围沿着不断增长的船只的迁移和投资下降，这种减少与异常有关 Col-III和Col-IV的沉积，似乎是周围粘合剂和迁移。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对于对血管壁投资的周围投资至关重要的方法。结合了这些创新的方法，我们将加深对周细胞皮层的机械理解细胞相互作用并激发人类疾病的新药物的发展。呢