Role for p27(Kip1), vascular smooth muscle cell migration

Background-Rapamycin is a potent inhibitor of smooth muscle cell (SMC) prol iferation and migration. Rapamycin-mediated inhibition of SMC proliferation is associated with upregulation of the cyclin-dependent kinase inhibitor p 27(Kip1). Previously, we showed that mixed embryonic fibroblasts obtained f rom p27(Kip1)(-/-) mice were relatively rapamycin-resistant, suggesting tha t p27(Kip1) plays an integral role in modulating the antiproliferative effe cts of rapamycin. We hypothesized that the antimigratory effect of rapamyci n may also be mediated by p27(Kip1) Methods and Results-Rapamycin (1 to 10 nmol/L) inhibited basic fibroblast g rowth factor-induced migration of wild-type (WT) but not p27(Kip1)(-/-) SMC s in a dose-dependent manner (P<0.05) in a modified Boyden chamber. The eff ects 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 day s 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), the signaling pathway(s) that regulates SMC migration.