Angiogenesis promoted by vascular endothelial growth factor: Regulation through alpha(1)beta(1) and alpha(2)beta(1) integrins

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a cytokine of central importance for the angiogenesis associated with cancers and other pathologies, Because angiogenesis often involves endothelial cell (EC) migration and proliferation within a collagen-rich extracellular matrix, we investigated the possibility that VEGF promotes neovascularization through regulation of collagen receptor expression, VEGF induced a 5- to 7-fold increase in dermal microvascular EC surface protein expression of two collagen receptors-the alpha(1) beta(1) and alpha(2) beta(1) integrins-through induction of mRNAs encoding the alpha(1) and alpha(2) subunits, In contrast, VEGF did not induce increased expression of the alpha(3) beta(1) integrin, which also has been implicated in collagen binding, Integrin alpha(1)-blocking and alpha(2)-blocking antibodies (Ab) each partially inhibited attachment of microvascular BC to collagen I, and anti-blocking Ab also inhibited attachment to collagen IV and laminin-l. Induction of alpha(1) beta(1) and alpha(2) beta(1) expression by VEGF promoted cell spreading on collagen I gels which mas abolished by a combination of alpha(1)-blocking and a blocking Abs. In vitro, a combination of alpha(1)-blocking and alpha(2)-blocking hhs markedly inhibited VEGF-driven angiogenesis; average cross-sectional area of individual new blood vessels was reduced 90% and average total new vascular area was reduced 82% without detectable effects on the pre-existing vasculature, These data indicate that induction of alpha(1) beta(1) and alpha(2) beta(1) expression by the EC is an important mechanism by which VEGF promotes angiogenesis and that alpha(1) beta(1) and alpha(2) beta(1) antagonists may prove effective in inhibiting VEGF-driven angiogenesis in cancers and other important pathologies.