Receptor‐independent role of the urokinase‐type plasminogen activator during arteriogenesis

ABSTRACT To define the role of the plasminogen activators (PAs) urokinase PA (uPA) and tissue PA (tPA) as well as the uPA receptor (uPAR) in arteriogenesis, we investigated their impact in a rabbit and mouse model of adaptive collateral artery growth. Collateral artery growth was induced by occlusion of the femoral artery in rabbit and wild‐type (WT) mice and in mice with targeted inactivation of uPA (uPA −/− ), tPA (tPA −/− ), or uPAR (uPAR −/− ). Northern blot results revealed a significant up‐regulation of uPA but not uPAR or tPA in the early phase of arteriogenesis in rabbit and WT mice. This up‐regulation on RNA level was followed by an increased protein level and enzymatic activity. Impaired perfusion recovery upon femoral artery ligation was observed by laser Doppler analysis in vivo in uPA‐deficient mice but not in uPAR or tPA deficiency compared with WT mice. Immunohistochemical studies revealed an association of leukocyte infiltration with arteriogenesis in WT mice that was strongly reduced in uPA −/− but not in uPAR‐ or tPA‐deficient mice. We conclude that arteriogenesis is promoted by an uPA‐mediated infiltration of leukocytes that is not dependent on uPAR.