Enhanced pathological angiogenesis in mice lacking beta(3) integrin or beta(3) and beta(5) integrins

Inhibition of a alpha (v)beta (3) or alpha (v)beta (5) integrin function has been reported to suppress neovascularization and tumor growth, suggesting that these integrins are critical modulators of angiogenesis. Here we report that mice lacking beta (3) integrins or both beta (3) and beta (5) integrins not only support tumorigenesis, but have enhanced tumor growth as well: Moreover, the tumors in these integrin-deficient mice display enhanced angiogenesis, strongly suggesting that neither beta (3) nor beta (5) integrins are essential for neovascularization. We, also observed that angiogenic responses to hypoxia and vascular endothelial growth factor (VEGF) are augmented significantly in the absence of beta (3) integrins. We found no evidence that the expression or functions of other integrins were altered as a consequence of the beta (3) deficiency, but we did observe elevated levels of VEGF receptor-2 (also called Flk-1) in beta (3)-null endothelial cells. These data indicate that a alpha (v)beta (3) and alpha (v)beta (5) integrins are not essential for vascular development or pathological angiogenesis and highlight the need for further evaluation of the mechanisms of action of alpha (v)-integrin antagonists in anti-angiogenic therapeutics.