VEGF-induced microvascular hyperpermeability not only represents a physiological consequence of angiogenesis, but also contributes to the development of diabetic retinopathy, ischemic heart disease, reperfusion injury, and tumor metastasis. The precise mechanisms by which VEGF modulates microvascular barrier function have not been established. Recent experimental evidence indicates that endothelial structures, namely VE-cadherin-composed adherens junctions and integrin-mediated cell-matrix focal adhesions are essential to the maintenance of endothelial barrier integrity. However, what molecular reactions mediate the structural changes and whether they are responsible for VEGF-induced microvascular leakage remain as questions. Among the reasons given to the shortcoming of such important information is the technical difficulty in making truly quantification of the permeability in living microvessels under native environment where the endothelium is anchored to the basement membrane. The overall goal of this study is to understand, at the microvascular level, the molecular mechanisms of endothelial cell-cell and cell-matrix interactions in response to VEGF. Intact perfused venules will be used as the primary model to quantitatively assess the barrier property and its regulatory pathways. A central hypothesis states that VEGF stimulation of microvascular endothelium induces biochemical and conformational changes at cell-cell and cell-matrix contacts, characterized by VE-cadherin-dependent junctional disorganization and FAK-mediated focal adhesion redistribution. The two structural components interact with the contractile cytoskeleton resulting in anchorage-dependent gap formation and microvascular hyperpermeability. This hypothesis will be tested by accomplishing the following specific aims: 1) to study the role and molecular basis of cell-cell adhesions in VEGF-induced permeability, 2) to examine the role and molecular basis of cell-matrix adhesions in VEGF-induced permeability, 3) to evaluate the relative importance of cell-cell vs. cell-matrix adhesions in the VEGF response, and 4) to investigate the integrative role of the contractile cytoskeleton in junctional and focal responses to VEGF. The study will provide new insights into the molecular basis of microvascular hyperpermeability. Identification and characterization of structural molecules that serve as ultimate effectors in VEGF-induced barrier dysfunction are fundamental to the understanding of mechanisms underlying angiogenesis, inflammation, and ischemic diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073324-03
Application #
6894659
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Goldman, Stephen
Project Start
2005-01-01
Project End
2009-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
3
Fiscal Year
2005
Total Cost
$340,875
Indirect Cost
Name
University of California Davis
Department
Surgery
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Rigor, Robert R; Shen, Qiang; Pivetti, Christopher D et al. (2013) Myosin light chain kinase signaling in endothelial barrier dysfunction. Med Res Rev 33:911-33
Yuan, Sarah Y; Shen, Qiang; Rigor, Robert R et al. (2012) Neutrophil transmigration, focal adhesion kinase and endothelial barrier function. Microvasc Res 83:82-8
Shen, Qiang; Rigor, Robert R; Pivetti, Christopher D et al. (2010) Myosin light chain kinase in microvascular endothelial barrier function. Cardiovasc Res 87:272-80
Shen, Qiang; Lee, Eugene S; Pitts, Robert L et al. (2010) Tissue inhibitor of metalloproteinase-2 regulates matrix metalloproteinase-2-mediated endothelial barrier dysfunction and breast cancer cell transmigration through lung microvascular endothelial cells. Mol Cancer Res 8:939-51
Shen, Qiang; Wu, Mack H; Yuan, Sarah Y (2009) Endothelial contractile cytoskeleton and microvascular permeability. Cell Health Cytoskelet 2009:43-50
Kumar, Puneet; Shen, Qiang; Pivetti, Christopher D et al. (2009) Molecular mechanisms of endothelial hyperpermeability: implications in inflammation. Expert Rev Mol Med 11:e19
Guo, Mingzhang; Daines, Dayle; Tang, Jing et al. (2009) Fibrinogen-gamma C-terminal fragments induce endothelial barrier dysfunction and microvascular leak via integrin-mediated and RhoA-dependent mechanism. Arterioscler Thromb Vasc Biol 29:394-400
Gaudreault, Nathalie; Perrin, Rachel M; Guo, Mingzang et al. (2008) Counter regulatory effects of PKCbetaII and PKCdelta on coronary endothelial permeability. Arterioscler Thromb Vasc Biol 28:1527-33
Breslin, Jerome W; Wu, Mack H; Guo, Mingzhang et al. (2008) Toll-like receptor 4 contributes to microvascular inflammation and barrier dysfunction in thermal injury. Shock 29:349-55
Guo, Mingzhang; Breslin, Jerome W; Wu, Mack H et al. (2008) VE-cadherin and beta-catenin binding dynamics during histamine-induced endothelial hyperpermeability. Am J Physiol Cell Physiol 294:C977-84

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