Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 24, Issue 11, Pages 2108-2114Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.ATV.0000143857.27408.de
Keywords
beta 3-integrin; VEGF; Flk-1; permeability; endothelium
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Objective -beta3-integrin deficiency has been implicated in increasing levels of Flk-1 expression on endothelial cells and enhancing vascular endothelial growth factor (VEGF)-induced angiogenesis. We determined the role of beta3-integrin in mediating VEGF-A -induced blood vessel permeability through Flk-1. Methods and Results - Using the Miles assay, we demonstrated that VEGF-A - induced plasma leakage was enhanced in beta3-null mice when compared with wild-type controls. This was not caused by any changes in blood vessel structure ( as detected by light or electron microscopy) or by changes in endothelial cell - cell adhesion proteins ( as determined by Western blot analysis, flow cytometry, and immunofluorescence). Circulating levels of VEGF, baseline blood vessel leakage, and leakage in response to an acute inflammatory stimulus were identical in wild-type and beta3-null mice. However, VEGF-A - induced leakage was abolished in beta3-null mice by the inhibition of Flk-1, indicating that the elevated levels of Flk-1 on beta3-null endothelial cells enhance VEGF-A - induced permeability. Conclusions - beta3-integrin - deficiency increases the sensitivity of endothelial cells to VEGF-A by elevating Flk-1 expression and, as a consequence, enhances VEGF-A - mediated permeability.
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