Integrin α2β1 is the required receptor for endorepellin angiostatic activity

Endorepellin, the C- terminal module of perlecan, has angiostatic activity. Here we provide definitive genetic and biochemical evidence that the functional endorepellin receptor is the alpha 2 beta 1 integrin. Notably, the specific endorepellin binding to the receptor was cation- independent and was mediated by the alpha 2 I domain. We show that the anti- angiogenic effects of endorepellin cannot occur in the absence of alpha 2 beta 1. Microvascular endothelial cells from alpha 2 beta 1(-/-) mice, but not those isolated from either wild- type or alpha 1 beta 1(-/-) mice, did not respond to endorepellin. Moreover, syngeneic Lewis lung carcinoma xenografts in alpha 2 beta 1(-/-) mice failed to respond to systemic delivery of endorepellin. In contrast, endorepellin inhibited tumor growth and angiogenesis in the wild- type mice expressing integrin alpha 2 beta 1. We conclude that the angiostatic effects of endorepellin in vivo are mediated by a specific interaction of endorepellin with the alpha 2 beta 1 integrin receptor.