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

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)

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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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:
    $ 38.91万
  • 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:
    $ 38.91万
  • 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:
    $ 38.91万
  • 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:
    $ 38.91万
  • 项目类别:
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
  • 财政年份:
    2016
  • 资助金额:
    $ 38.91万
  • 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:
    $ 38.91万
  • 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:
    $ 38.91万
  • 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:
    $ 38.91万
  • 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:
    $ 38.91万
  • 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:
    $ 38.91万
  • 项目类别:

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