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， 阿尔茨海默氏病和癌症的恶化是由于血管功能的缺陷造成的。 周细胞-内皮细胞相互作用。尽管周细胞-内皮细胞相互作用在人类中的重要性 健康和疾病，关键的知识差距存在的机制，周细胞被招募， 并保留在发育中的血管上的特定位置（即沉积）。我们和其他人以前 显示血管内皮生长因子-A（VEGF-A）途径，通过其负性受体之一Flt- 1（VEGF受体-1）-特别是可溶性Flt-1（sFlt-1）-在内皮细胞中产生空间异质性， 促进有效血管形成的表型（即“尖端”细胞发芽并形成新的血管分支， “茎”细胞增殖并有助于血管伸长）。这种内皮细胞表型 异质性有助于建立周细胞投资的这些特定位点并没有很好地定义。 此外，差距连接蛋白连接蛋白43（Cx43）介导了细胞间周细胞-内皮细胞的相互作用。 血管形成，但Cx43如何调节VEGF-A下游的周细胞投资尚不清楚 发信号。本研究的总体目标是调查新的假设，即sFlt-1调节 VEGF-A信号传导通过（i）提供周细胞-内皮细胞相互作用的基本调节 协调内皮细胞表型异质性，和（ii）协调Cx43的空间表达， 周细胞和内皮细胞。我们将通过结合创新的体外、离体和体内试验来验证这一假设。 体内模型与尖端的分析方法，以扩大我们的初步观察，显示增加 当VEGF信号被破坏时，周细胞滞留在特定的位置，而当VEGF信号被破坏时，Cx43表达的“热点”在特定的位置。 血管分支点，周细胞附着于此。合作者将提供Cx43生物学方面的专业知识， 新的成像方法，将是必不可少的彻底调查周细胞投资到血液 血管壁结合这些创新的方法，我们将加深我们的机械理解， 周细胞-内皮细胞的相互作用，并启发开发用于人类疾病的新药。