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Am J Physiol Heart Circ Physiol (April 21, 2006). doi:10.1152/ajpheart.01042.2005
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Submitted on October 3, 2005
Accepted on January 31, 2006

LRP and &agr;v&bgr;3 mediate tPA-activation of smooth muscle cells

Sa'ed Akkawi1, Taher Nassar1, Mark Tarshis2, Douglas B. Cines3, and Abd Al-Roof Higazi4*

1 Clinical Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel
2 Interdepartmental Unit, Hebrew University-Hadassah Medical School, Jerusalem, Israel
3 Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
4 Clinical Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel; Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States

* To whom correspondence should be addressed. E-mail: higazi{at}mail.med.upenn.edu.

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-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 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 minutes causing the cells to become refractory to re-addition of tPA. LRP and {alpha}v{beta}3 return to the cell surface by 90 minutes restoring cell responsiveness to tPA. PAI-1 and the PAI-1-derived hexapeptide EEIIMD abolish the vasocontracile 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.




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