RECEPTOR-INDEPENDENT ROLE OF UROKINASE-TYPE PLASMINOGEN-ACTIVATOR IN PERICELLULAR PLASMIN AND MATRIX METALLOPROTEINASE PROTEOLYSIS DURING VASCULAR WOUND-HEALING IN MICE

It has been proposed that the urokinase receptor (u-PAR) is essential for the various biological roles of urokinase-type plasminogen activat or (u-PA) in vivo, and that smooth muscle cells require u-PA for migra tion during arterial neointima formation. The present study was undert aken to evaluate the role of u-PAR during this process in mice with ta rgeted disruption of the u-PAR gene (u-PAR(-/-)). Surprisingly, u-PAR deficiency did not affect arterial neointima formation, neointimal cel l accumulation, or migration of smooth muscle cells, Indeed, topograph ic analysis of arterial wound healing after electric injury revealed t hat u-PAR(-/-) smooth muscle cells, originating from the uninjured bor ders, migrated over a similar distance and at a similar rate into the necrotic center of the wound as wild-type (u-PAR(+/+)) smooth muscle c ells, In addition, u-PAR deficiency did not impair migration of wounde d cultured smooth muscle cells in vitro. There were no genotypic diffe rences in reendothelialization of the vascular wound. The minimal role of u-PAR in smooth muscle cell migration was not because of absent ex pression, since wild-type smooth muscle cells expressed u-PAR mRNA and functional receptor in vitro and in vivo. Pericellular plasmin proteo lysis, evaluated by degradation of I-125-labeled fibrin and activation of zymogen matrix metalloproteinases, was similar for u-PAR(-/-) and u-PAR(+/+) cells, Immunoelectron microscopy of injured arteries in viv o revealed that u-PA was bound on the cell surface of u-PAR(+/+) cells , whereas it was present in the pericellular space around u-PAR(-/-) c ells. Taken together, these results suggest that binding, of u-PA to u -PAR is not required to provide sufficient pericellular u-PA-mediated plasmin proteolysis to allow cellular migration into a vascular wound.