LRP and αvβ3 mediate tPA activation of smooth muscle cells

Tissue-type plasminogen activator (tPA) regulates vascular contractility through the low-density lipoprotein-related receptor (LRP), and this effect is inhibited by plasminogen activator inhibitor type 1 (PAI-1). We now report that tPA-mediated vasocontraction also requires the integrin alpha(v)beta(3). tPA-induced contraction of rat aortic rings is inhibited by the Arg-Gly-Asp (RGD) peptide and by monoclonal anti-alpha(v)beta(3) antibody. tPA induces the formation of a complex between LRP and alpha(v)beta(3) in vascular smooth muscle cells. The three proteins are internalized within 10 min, causing the cells to become refractory to the readdition of tPA. LRP and alpha(v)beta(3) return to the cell surface by 90 min, restoring cell responsiveness to tPA. PAI-1 and the PAI-1-derived hexapeptide EEIIMD abolish the vasocontractile activity of tPA and inhibit the tPA-mediated interaction between LRP and alpha(v)beta(3). tPA induces calcium mobilization from intracellular stores in vascular smooth muscle cells, and this effect is inhibited by PAI- 1, RGD, and antibodies to both LRP and alpha(v)beta(3). These data indicate that tPA-mediated vasocontraction involves the coordinated interaction of LRP with alpha(v)beta(3). Delineating the mechanism underlying these interactions and the nature of the signals transduced may provide new tools to regulate vascular tone and other consequences of tPA-mediated signaling.