LRP and αvβ3 mediate tPA activation of smooth muscle cells

Sa'ed Akkawi, Taher Nassar, Mark Tarshis, Douglas B. Cines, Abd Al Roof Higazi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

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 vβ3. tPA-induced contraction of rat aortic rings is inhibited by the Arg-Gly-Asp (RGD) peptide and by monoclonal anti-αvβ3 antibody. tPA induces the formation of a complex between LRP and αvβ3 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 αvβ3 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 αvβ3. 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 αvβ3. These data indicate that tPA-mediated vasocontraction involves the coordinated interaction of LRP with αvβ3. 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.

Original languageAmerican English
Pages (from-to)H1351-H1359
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume291
Issue number3
DOIs
StatePublished - 2006
Externally publishedYes

Keywords

  • Integrins
  • Lipoprotein-related receptor
  • Tissue-type plasminogen activator
  • Vasoactivity

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