Role for p27Kip1 in Vascular Smooth Muscle Cell Migration

Background—Rapamycin is a potent inhibitor of smooth muscle cell (SMC) proliferation and migration. Rapamycin-mediated inhibition of SMC proliferation is associated with upregulation of the cyclin-dependent kinase inhibitor p27Kip1. Previously, we showed that mixed embryonic fibroblasts obtained from p27Kip1(2/2) mice were relatively rapamycin-resistant, suggesting that p27Kip1 plays an integral role in modulating the antiproliferative effects of rapamycin. We hypothesized that the antimigratory effect of rapamycin may also be mediated by p27Kip1. Methods and Results—Rapamycin (1 to 10 nmol/L) inhibited basic fibroblast growth factor–induced migration of wild-type (WT) but not p27Kip1(2/2) SMCs in a dose-dependent manner (P,0.05) in a modified Boyden chamber. The effects of rapamycin on aortic SMC explant migration were also studied with WT, p27(1/2), and p27(2/2) mice. Rapamycin 4 mg · kg21 · d21 IP for 5 days inhibited SMC migration by 90 % in the WT and p27Kip1(1/2) (P,0.05) but not p27Kip1(2/2) animals. Conclusions—Lack of p27Kip1 reduces rapamycin-mediated inhibition of SMC migration. These novel findings suggest a role for p27Kip1 in the signaling pathway(s) that regulates SMC migration. (Circulation. 2001;103:2967-2972.) Key Words: muscle, smooth n cells n inhibitors n rapamycin Vascular smooth muscle cell (SMC) migration is believedto play a major role in the pathogenesis of many vascular diseases, including atherosclerosis and restenosi