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This Article Full Text Full Text (PDF) All Versions of this Article: 291/3/H1351    most recent 01042.2005v3 01042.2005v2 01042.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Akkawi, S. Articles by Higazi, A. A.-R. Search for Related Content PubMed PubMed Citation Articles by Akkawi, S. Articles by Higazi, A. A.-R.

LRP and _v3 mediate tPA activation of smooth muscle cells

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

Submitted 3 October 2005 ; accepted in final form 17 February 2006

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 _v3. tPA-induced contraction of rat aortic rings is inhibited by the Arg-Gly-Asp (RGD) peptide and by monoclonal anti-_v3 antibody. tPA induces the formation of a complex between LRP and _v3 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 _v3 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 _v3. 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 _v3. These data indicate that tPA-mediated vasocontraction involves the coordinated interaction of LRP with _v3. 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.

lipoprotein-related receptor; tissue-type plasminogen activator; integrins; vasoactivity

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