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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2108.)
© 2004 American Heart Association, Inc.

Vascular Biology

ß3-Integrin Regulates Vascular Endothelial Growth Factor-A–Dependent Permeability

Stephen D. Robinson; Louise E. Reynolds; Lorenza Wyder; Daniel J. Hicklin; Kairbaan M. Hodivala-Dilke

From the Cell Adhesion and Disease/Tumour Biology Laboratory (S.D.R., L.E.R., K.M.H.-D.), Cancer Research UK Clinical Centre, Queen Mary’s School of Medicine & Dentistry at Barts & The London, John Vane Science Centre, Charterhouse Square, London; Novartis Institute for Biomedical Research (L.W.), Angiogenesis Programme, Basel, Switzerland; and ImClone Systems Inc (D.J.H.), New York, NY.

Correspondence to Stephen D. Robinson, Cell Adhesion and Disease/Tumour Biology Laboratory, Cancer Research UK Clinical Centre, Queen Mary’s School of Medicine & Dentistry at Barts & The London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom. E-mail s.d.robinson{at}cancer.org.uk

Objective— ß3-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 ß3-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 ß3-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 ß3-null mice. However, VEGF-A–induced leakage was abolished in ß3-null mice by the inhibition of Flk-1, indicating that the elevated levels of Flk-1 on ß3-null endothelial cells enhance VEGF-A–induced permeability.

Conclusions— ß3-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.

Blood vessels in ß3-integrin–deficient mice are histologically normal and functionally intact. However, they express elevated levels of Flk-1 and are more sensitive than wild-type blood vessels to VEGF-A–induced permeability, but not to permeability induced by acute inflammatory agents.

Key Words: ß3-integrin • VEGF • Flk-1 • permeability • endothelium

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