Regulation of vascular homeostasis depends upon collaboration between cells
of the vessel wall and blood coagulation system. A direct interaction betw
een integrin alpha(v)beta(3) on endothelial cells and smooth muscle cells a
nd prothrombin, the pivotal proenzyme of the blood coagulation system, is d
emonstrated and activation of the integrin is required for receptor engagem
ent. Evidence that prothrombin is a ligand for alpha(v)beta(3) on these cel
ls include: (a) prothrombin binds to purified alpha(v)beta(3) via a RGD rec
ognition specificity; (b) prothrombin supports alpha(v)beta(3)-mediated adh
esion of stimulated endothelial cells and smooth muscle cells; and (c) endo
thelial cells, either in suspension and in a monolayer, recognize soluble p
rothrombin via alpha(v)beta(3). alpha(v)beta(3)-mediated cell adhesion to p
rothrombin, but not to fibrinogen, required activation of the receptor. Thu
s, the functionality of the alpha(v)beta(3) receptor is ligand defined, and
prothrombin and fibrinogen represent activation-dependent and activation-i
ndependent ligands. Activation of alpha(v)beta(3) could be induced not only
by model agonists, PMA and Mn2+, but also by a physiologically relevant ag
onist, 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 signif
icant role in the maintenance of hemostasis; and, at a general level, ligan
d selection by alpha(v)beta(3) may be controlled by the activation state of
this integrin.