Flt-VEGF-Cx43 Regulation of Vascular Pericyte Investment

Flt-VEGF-Cx43 对血管周细胞投资的调节

基本信息

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 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.
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项目成果

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John Christopher Chappell其他文献

John Christopher Chappell的其他文献

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{{ truncateString('John Christopher Chappell', 18)}}的其他基金

A Tissue-Specific Soluble Platelet-Derived Growth Factor Receptor-beta Isoform Retains Functional Capacity
组织特异性可溶性血小板衍生生长因子受体-β亚型保留功能能力
  • 批准号:
    10668031
  • 财政年份:
    2023
  • 资助金额:
    $ 38.58万
  • 项目类别:
Integrated Virginia Research Training Centers in KUH (IGNITE KUH)
KUH 弗吉尼亚综合研究培训中心 (IGNITE KUH)
  • 批准号:
    10285526
  • 财政年份:
    2021
  • 资助金额:
    $ 38.58万
  • 项目类别:
Integrated Virginia Research Training Centers in KUH (IGNITE KUH)
KUH 弗吉尼亚综合研究培训中心 (IGNITE KUH)
  • 批准号:
    10657702
  • 财政年份:
    2021
  • 资助金额:
    $ 38.58万
  • 项目类别:
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:
    10449094
  • 财政年份:
    2019
  • 资助金额:
    $ 38.58万
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    $ 38.58万
  • 项目类别:
The Role of Vascular Flt-1 in Endothelial-Pericyte Interactions
血管 Flt-1 在内皮-周细胞相互作用中的作用
  • 批准号:
    8969688
  • 财政年份:
    2014
  • 资助金额:
    $ 38.58万
  • 项目类别:
The Role of Vascular Flt-1 in Endothelial-Pericyte Interactions
血管 Flt-1 在内皮-周细胞相互作用中的作用
  • 批准号:
    8467035
  • 财政年份:
    2012
  • 资助金额:
    $ 38.58万
  • 项目类别:
The Role of Vascular Flt-1 in Endothelial-Pericyte Interactions
血管 Flt-1 在内皮-周细胞相互作用中的作用
  • 批准号:
    8242399
  • 财政年份:
    2012
  • 资助金额:
    $ 38.58万
  • 项目类别:
Flt-1 (VEGFR-1) Regulation of Endothelial Cell Sprouting and Vessel Morphogenesis
Flt-1 (VEGFR-1) 调节内皮细胞出芽和血管形态发生
  • 批准号:
    7614747
  • 财政年份:
    2009
  • 资助金额:
    $ 38.58万
  • 项目类别:
Flt-1 (VEGFR-1) Regulation of Endothelial Cell Sprouting and Vessel Morphogenesis
Flt-1 (VEGFR-1) 调节内皮细胞出芽和血管形态发生
  • 批准号:
    7771689
  • 财政年份:
    2009
  • 资助金额:
    $ 38.58万
  • 项目类别:
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