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PLoS One. 2012;7(5):e37195. doi: 10.1371/journal.pone.0037195. Epub 2012 May 11.

Vitronectin increases vascular permeability by promoting VE-cadherin internalization at cell junctions.

Author information

1
Drug Discovery Research Center of Luzhou Medical College, Luzhou Medical College, Luzhou, Sichuan, People's Republic of China.

Abstract

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-α(V)β(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.

PMID:
22606350
PMCID:
PMC3350505
DOI:
10.1371/journal.pone.0037195
[Indexed for MEDLINE]
Free PMC Article

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