UROKINASE BUT NOT TISSUE-PLASMINOGEN ACTIVATOR MEDIATES ARTERIAL NEOINTIMA FORMATION IN MICE

To define the role of the plasminogen activators (PAs) tissue PA (t-PA ) and urokinase PA (u-PA) in vascular wound healing, neointima formati on and reendothelialization were evaluated after electric or mechanica l arterial injury in mice with a single or combined deficiency of t-PA (t-PA(-/-)) and/or u-PA (u-PA(-/-)). In both models, neointima format ion and neointimal cell accumulation were reduced in u-PA(-/-) and in t-PA(-/-)/u-PA(-/-) arteries but not in t-PA(-/-) arteries. The electr ic injury model was used to characterize the underlying cellular mecha nisms. Topographic analysis of vascular wound healing in electrically injured wild-type and t-PA(-/-) arteries revealed a similar degree of migration of smooth muscle cells from the noninjured borders into the necrotic center. In contrast, in u-PA(-/-) and t-PA(-/-)/u-PA(-/-) art eries, smooth muscle cells accumulated at the uninjured borders but fa iled to migrate into the necrotic center. Cultured u-PA(-/-) but not t -PA(-/-) smooth muscle cells also failed to migrate in vitro after scr ape wounding. Proliferation of smooth muscle cells was not affected by PA deficiency. Reendothelialization after electric injury was similar in all genotypes. In situ analysis revealed markedly elevated u-PA zy mographic activity, mRNA, and immunoreactivity in smooth muscle cells, endothelial cells, and leukocytes within 1 week after injury, eg, whe n cells migrated into the wound. Thus, u-PA plays a significant role i n vascular wound healing and arterial neointima formation after injury , most likely by affecting cellular migration.