Journal
CIRCULATION RESEARCH
Volume 94, Issue 9, Pages 1227-1234Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000126567.75232.46
Keywords
urokinase-type plasminogen activator receptor; high molecular weight kininogen; endothelial cells; apoptosis; angiogenesis
Funding
- NCI NIH HHS [R01 CA63938] Funding Source: Medline
- NHLBI NIH HHS [T32 HL 07777] Funding Source: Medline
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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 alpha(v)beta(3) or alpha(5)beta(1), 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.
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