LRP and alphavbeta3 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 alphavbeta3. tPA-induced contraction of rat aortic rings is inhibited by the Arg-Gly-Asp (RGD) peptide and by monoclonal anti-alphavbeta3 antibody. tPA induces the formation of a complex between LRP and alphavbeta3 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 alphavbeta3 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 alphavbeta3. 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 alphavbeta3. These data indicate that tPA-mediated vasocontraction involves the coordinated interaction of LRP with alphavbeta3. 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.
Department of Clinical Biochemistry, and Interdepartmental Unit, Hadassah University Hospital and Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Sa'ed
S
Akkawi
Taher
T
Nassar
Mark
M
Tarshis
Douglas B
DB
Cines
Abd Al-Roof
AA
Higazi
D000818:Animals; D002118:Calcium / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D010959:Tissue Plasminogen Activator / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D039302:Integrin alphaVbeta3; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009842:Oligopeptides; D017395:Plasminogen Activator Inhibitor 1; C513663:glutamyl-glutamyl-isoleucyl-isoleucyl-methionyl-aspartic acid; C047981:arginyl-glycyl-aspartic acid; D010959:Tissue Plasminogen Activator; D002118:Calcium