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)： 血管向全身输送营养和氧气，以维持每个组织和组织的健康 管风琴。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 血管的生长和维持将指导治疗策略的发展，以治疗衰弱和 通常与血管异常相关的危及生命的疾病。周细胞是血管周围细胞， 包裹并投资于生长中的血管，为血管的稳定性、成熟度提供必要的调节 和宁静。各种病理，如新生儿颅内出血，糖尿病视网膜病变， 阿尔茨海默氏症和癌症因血管功能障碍而加剧 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，关于周细胞被招募到 并保留在特定地点(即投资)，用于发展血管。我们和其他人之前 研究表明，血管内皮细胞生长因子-A(VEGF-A)途径是通过其负性受体Flt-A介导的。 1(血管内皮生长因子受体-1)-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”细胞萌发并形成新的血管分支， “柄”细胞增殖并有助于血管的延长)。确切地说，这种内皮细胞的表型 异质性有助于建立这些特定的周细胞投资部位，目前还没有很好的定义。 此外，缝隙连接蛋白43(Cx43)介导了周细胞-内皮细胞之间的相互作用。 血管形成，但尚不清楚Cx43如何调控血管内皮生长因子-A下游的周细胞投资 发信号。这项研究的总体目标是调查sflt-1调节 血管内皮生长因子-A信号通过(I)对周细胞-内皮细胞相互作用提供必要的调节 内皮细胞表型异质性的协调，以及(Ii)Cx43的协调空间表达 周细胞和内皮细胞。我们将通过结合创新的体外、体外和体内实验来检验这一假说。 使用尖端分析方法扩展我们的初步观察的活体模型显示 当血管内皮生长因子信号被干扰时，周细胞滞留在特定位置，以及Cx43在 周细胞投资的血管分支点。合作者将提供Cx43生物学和 对深入研究周细胞进入血液的投资至关重要的新的成像方法 血管壁。结合这些创新方法，我们将加深对 周细胞-内皮细胞相互作用，并启发人类疾病新药的开发。