Journal
PLOS ONE
Volume 7, Issue 5, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0037195
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Funding
- AHA National Scientist Development Grant [10SDG2570037]
- Research Council Grant from the University of Missouri [URC-10-001-Wu]
- National Natural Science Foundation of China [81172050]
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Background: Cross-talk between integrins and cadherins regulates cell function. We tested the hypothesis that vitronectin (VN), a multi-functional adhesion molecule present in the extracellular matrix and plasma, regulates vascular permeability via effects on VE-cadherin, a critical regulator of endothelial cell (EC) adhesion. Methodology/Principal Findings: Addition of multimeric VN (mult VN) significantly increased VE-cadherin internalization in human umbilical vein EC (HUVEC) monolayers. This effect was blocked by the anti-alpha(V)beta(3) antibody, pharmacological inhibition and knockdown of Src kinase. In contrast to mult VN, monomeric VN did not trigger VE-cadherin internalization. In a modified Miles assay, VN deficiency impaired vascular endothelial growth factor-induced permeability. Furthermore, ischemia-induced enhancement of vascular permeability, expressed as the ratio of FITC-dextran leakage from the circulation into the ischemic and non-ischemic hindlimb muscle, was significantly greater in the WT mice than in the Vn(-/-) mice. Similarly, ischemia-mediated macrophage infiltration was significantly reduced in the Vn(-/-) mice vs. the WT controls. We evaluated changes in the multimerization of VN in ischemic tissue in a mouse hindlimb ischemia model. VN plays a previously unrecognized role in regulating endothelial permeability via conformational- and integrin-dependent effects on VE-cadherin trafficking. Conclusion/Significance: These results have important implications for the regulation of endothelial function and angiogenesis by VN under normal and pathological conditions.
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