Role for p27 Kip1 in Vascular Smooth Muscle Cell Migration

Abstract

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 p27 Kip1 . Previously, we showed that mixed embryonic fibroblasts obtained from p27 Kip1 (−/−) mice were relatively rapamycin-resistant, suggesting that p27 Kip1 plays an integral role in modulating the antiproliferative effects of rapamycin. We hypothesized that the antimigratory effect of rapamycin may also be mediated by p27 Kip1 . Methods and Results —Rapamycin (1 to 10 nmol/L) inhibited basic fibroblast growth factor–induced migration of wild-type (WT) but not p27 Kip1 (−/−) 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(+/−), and p27(−/−) mice. Rapamycin 4 mg · kg −1 · d −1 IP for 5 days inhibited SMC migration by 90% in the WT and p27 Kip1 (+/−) ( P <0.05) but not p27 Kip1 (−/−) animals. Conclusions —Lack of p27 Kip1 reduces rapamycin-mediated inhibition of SMC migration. These novel findings suggest a role for p27 Kip1 in the signaling pathway(s) that regulates SMC migration.