on September 2, 2004
Published online before print September 2, 2004, doi: 10.1161/01.ATV.0000143857.27408.de
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Submitted on April 8, 2004
Accepted on August 3, 2004
3-Integrin Regulates Vascular Endothelial Growth Factor-A-Dependent Permeability
Stephen D. Robinson *;
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.
* To whom correspondence should be addressed. E-mail: s.d.robinson{at}cancer.org.uk.
Objective--
3-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 3-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 3-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 3-null mice. However, VEGF-A-induced leakage was abolished in 3-null mice by the inhibition of Flk-1, indicating that the elevated levels of Flk-1 on 3-null endothelial cells enhance VEGF-A-induced permeability.
Conclusions--3-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.
Key words:
3-integrin •
VEGF •
Flk-1 •
permeability •
endothelium
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