On the mechanism of thrombin-induced angiogenesis: involvement of αvβ3-integrin

Thrombin has been reported to be a potent angiogenic factor both in vitro and in vivo, and many of the cellular effects of thrombin may contribute to activation of angiogenesis. In this report we show that thrombin-treatment of human endothelial cells increases mRNA and protein levels of αvβ3-integrin. This thrombin-mediated effect is specific, dose dependent, and requires the catalytic site of thrombin. In addition, thrombin interacts with αvβ3 as demonstrated by direct binding of αvβ3 protein to immobilized thrombin. This interaction of thrombin with αvβ3-integrin, which is an angiogenic marker in vascular tissue, is of functional significance. Immobilized thrombin promotes endothelial cells attachment, migration, and survival. Antibody to αvβ3 or a specific peptide antagonist to αvβ3 can abolish all these αvβ3-mediated effects. Furthermore, in the chick chorioallantoic membrane system, the antagonist peptide to αvβ3 diminishes both basal and the thrombin-induced angiogenesis. These results support the pivotal role of thrombin in activation of endothelial cells and angiogenesis and may be related to the clinical observation of neovascularization within thrombi.