Cell contact-dependent activation of alpha 3 beta 1 integrin modulates endothelial cell responses to thrombospondin-1

Thrombospondin-1 (TSP1) can inhibit angiogenesis by interacting with endoth elial cell CD36 or proteoglycan receptors. We have now identified alpha 3 b eta 1 integrin as an additional receptor for TSP1 that modulates angiogenes is and the in vitro behavior of endothelial cells. Recognition of TSP1. and an alpha 3 beta 1 integrin-binding peptide from TSP1 by normal endothelial cells is induced after loss of cell-cell contact or ligation of CD98. Alth ough confluent endothelial cells do not spread on a TSP1 substrate, alpha 3 beta 1 integrin mediates efficient spreading on TSP1 substrates of endothe lial cells deprived of cell-cell contact or vascular endothelial cadherin s ignaling. Activation of this integrin is independent of proliferation, but ligation of the alpha 3 beta 1 integrin modulates endothelial cell prolifer ation. In solution, both intact TSP1 and the alpha 3 beta 1 integrin-bindin g peptide from TSP1 inhibit proliferation of sparse endothelial cell cultur es independent of their CD36 expression. However, TSP1 or the same peptide immobilized on the substratum promotes their proliferation. The TSP1 peptid e, when added in solution, specifically inhibits endothelial cell migration and inhibits angiogenesis in the chick chorioallantoic membrane, whereas a fragment of TSP1 containing this sequence stimulates angiogenesis. Therefo re, recognition of immobilized TSP1 by alpha 3 beta 1 integrin may stimulat e endothelial cell proliferation and angiogenesis. Peptides that inhibit th is interaction are a novel class of angiogenesis inhibitors.