Flt-VEGF-Cx43 Regulation of Vascular Pericyte Investment

Flt-VEGF-Cx43 对血管周细胞投资的调节

• 批准号: 9324428
• 负责人: John Christopher Chappell
• 金额: $ 38.58万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324428
• 关键词: Affect; Alzheimer' s Disease; Back; Biology; Blood Vessels; CSPG4 gene; Cell Communication; Cell Polarity; Cells; Clinical; Confocal Microscopy; Connexin 43; Connexins; Cytoskeleton; Data; Defect; Destinations; Development; Diabetic Retinopathy; Disease; Embryo; Endothelial Cells; Genetic; Growth; Growth Factor Gene; Health; Heterogeneity; Homing; Hot Spot; Human; Image; In Vitro; Intercellular Junctions; Intracranial Hemorrhages; Investigation; Investments; KDR gene; Knowledge; Life; Location; Maintenance; Malignant Neoplasms; Mediating; Modeling; Modification; Molecular; Molecular Biology; Mus; Mutation; Neonatal; Nutrient; Organ; Oxygen; Pathology; Pathway interactions; Patients; Pattern; Pericytes; Pharmaceutical Preparations; Phenotype; Process; Proliferating; Protein Isoforms; Recruitment Activity; Regulation; Reporter; Research; Resolution; Retina; Role; Signal Transduction; Site; Skin; Spatial Distribution; Specific qualifier value; Specimen; Subfamily lentivirinae; Surface; Testing; Time; Tissues; VEGFA gene; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vascular System; Work; abstracting; base; blood vessel development; cell type; embryonic stem cell; genetic inhibitor; human disease; imaging modality; improved; in vivo; in vivo Model; innovation; insight; knock-down; migration; mutant; novel; novel therapeutics; postnatal; public health relevance; receptor; therapeutic development; time use; tool

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 cancer are exacerbated by disrupted vascular function 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 gap junction protein Connexin43 (Cx43) mediates pericyte-endothelial cell interactions during blood vessel formation, but it is not clear how Cx43 modulates pericyte investment downstream of VEGF-A signaling. The overall objective of this research is to investigate the novel hypothesis that sFlt-1 modulates VEGF-A signaling to provide essential regulation of pericyte-endothelial cell interactions through (i) coordination of endothelial phenotypic heterogeneity, and (ii) orchestrated spatial expression of Cx43 on pericytes and endothelial cells. 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 increased pericyte retention at specific locations when VEGF signaling is disrupted, and “hot spots” of Cx43 expression at blood vessel branch points where pericytes invest. Collaborators will provide expertise in Cx43 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， 阿尔茨海默氏病和癌症因缺陷而导致的血管功能破坏而加剧 周细胞内皮细胞相互作用。尽管人类的周细胞膜互动很重要 健康和疾病，知识上存在关键的差距，招募周细胞的机制 并保留在开发血管的特定位置（即投资）。我们和其他人以前有 表明血管内皮生长因子A（VEGF-A）途径是通过其负受体之一 1（VEGF受体1） - 固体FLT-1（SFLT-1） - 在内皮细胞中产生空间异质性 表型促进有效的血管形成（即“尖端”细胞萌芽并形成新的血管分支， “茎”细胞增殖并导致血管伸长）。正是这种内皮表型如何 异质性有助于建立这些特定的周围投资地点。 此外，间隙连接蛋白连接蛋白43（CX43）介导周围的细胞 - 内皮细胞相互作用 血管形成，但尚不清楚CX43如何调节vegf-a下游的周围投资 信号。这项研究的总体目的是研究SFLT-1调节的新假设 VEGF-A信号传导通过（i）提供对周细胞 - 内皮细胞相互作用的基本调节 内皮表型异质性的协调，以及（ii）CX43的空间表达 周细胞和内皮细胞。我们将通过在体外，Ex Vivo和In结合创新的创新来检验这一假设 使用最先进的分析方法的体内模型扩展了我们的初步观察结果 当VEGF信号被破坏时，在特定位置的周围保留率，CX43表达的“热点” 血管分支机构投资的点。合作者将在CX43生物学和中提供专业知识 新颖的成像方法对于对血液投资的全面研究至关重要 船墙。结合这些创新的方法，我们将加深对机械的理解 周细胞皮细胞相互作用，并激发人类疾病的新药物的发展。