LRP and α v β 3 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 α v β 3 . tP...

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Veröffentlicht in:American journal of physiology. Heart and circulatory physiology 2006-09, Vol.291 (3), p.H1351-H1359
Hauptverfasser: Akkawi, Sa'ed, Nassar, Taher, Tarshis, Mark, Cines, Douglas B., Higazi, Abd Al-Roof
Format: Artikel
Sprache:eng
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Zusammenfassung: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 α v β 3 . tPA-induced contraction of rat aortic rings is inhibited by the Arg-Gly-Asp (RGD) peptide and by monoclonal anti-α v β 3 antibody. tPA induces the formation of a complex between LRP and α v β 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 α v β 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 α v β 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 α v β 3. These data indicate that tPA-mediated vasocontraction involves the coordinated interaction of LRP with α v β 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.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.01042.2005