Urokinase-type plasminogen activator receptor is involved in mediating the apoptotic effect of cleaved high molecular weight kininogen in human endothelial cells

Dian J. Cao, Yan Lin Guo, Robert W. Colman

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Cleaved high molecular weight kininogen (HKa) has been shown to inhibit in vivo neovascularization and induce apoptosis of endothelial cells. We have shown that HKa-induced apoptosis correlated with its antiadhesive effect and was regulated by extracellular matrix (ECM) proteins. In this study, we identified the urokinase-type plasminogen activator receptor (uPAR) as a target of HKa activity at the endothelial cell surface. Anti-uPAR antibodies blocked the apoptotic effect of HKa. Further studies revealed that uPAR formed a signaling complex containing integrin αvβ3 or α5β1, caveolin, and Src kinase Yes in endothelial cells. HKa physically disrupted the formation of this complex in a manner that paralleled its apoptotic effect. For the first time, our results provide a mechanistic explanation for the previous observation that HKa selectively induces apoptosis of endothelial cells grown on vitronectin, but not cells grown on fibronectin. These data also resolve the controversial role of uPAR in mediating the apoptotic and antiadhesive activities of HKa.

Original languageEnglish (US)
Pages (from-to)1227-1234
Number of pages8
JournalCirculation research
Volume94
Issue number9
DOIs
StatePublished - May 14 2004

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Keywords

  • Angiogenesis
  • Apoptosis
  • Endothelial cells
  • High molecular weight kininogen
  • Urokinase-type plasminogen activator receptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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