Activation of αVβ3 on vascular cells controls recognition of prothrombin

Regulation of vascular homeostasis depends upon collaboration between cells of the vessel wall and blood coagulation system. A direct interaction between integrin alpha(v)beta(3) on endothelial cells and smooth muscle cells and prothrombin, the pivotal proenzyme of the blood coagulation system, is demonstrated and activation of the integrin is required for receptor engagement. Evidence that prothrombin is a ligand for alpha(v)beta(3) on these cells include: (a) prothrombin binds to purified alpha(v)beta(3) via a RGD recognition specificity; (b) prothrombin supports alpha(v)beta(3)-mediated adhesion of stimulated endothelial cells and smooth muscle cells; and (c) endothelial cells, either in suspension and in a monolayer, recognize soluble prothrombin via alpha(v)beta(3). alpha(v)beta(3)-mediated cell adhesion to prothrombin, but not to fibrinogen, required activation of the receptor. Thus, the functionality of the alpha(v)beta(3) receptor is ligand defined, and prothrombin and fibrinogen represent activation-dependent and activation-independent ligands. Activation of alpha(v)beta(3) could be induced not only by model agonists, PMA and Mn2+, but also by a physiologically relevant agonist, ADP. Inhibition of protein kinase C and calpain prevented activation of alpha(v)beta(3) on vascular cells, suggesting that these molecules are involved in the inside-out signaling events that activate the integrin. The capacity of alpha(v)beta(3) to interact with prothrombin may play a significant role in the maintenance of hemostasis; and, at a general level, ligand selection by alpha(v)beta(3) may be controlled by the activation state of this integrin.