Aim: Calcium channel blockers (CCBs) inhibit the migration of vascular smooth muscle cells (VSMC) by mechanisms that remain poorly understood. The purpose of the present study was to characterize the signaling mechanisms by which CCBs inhibit VSMC migration.
Methods and results: Nifedipine potently inhibited platelet-derived growth factor (PDGF)-induced chemotaxis, collagen I-induced haptotaxis, and wound-induced migration of human aortic VSMC. In addition, nifedipine inhibited PDGF-induced membrane ruffling and lamellipodium formation. PDGF-induced VSMC migration was significantly inhibited by PP2, a selective inhibitor of the Src kinase family, and was also significantly inhibited by the expression of kinase-inactive Src, suggesting that Src is required for VSMC migration. Nifedipine also inhibited PDGF-induced Src activation (by 60+/-4% with 30 microM) and tyrosinephosphorylation of Cas, paxillin, and cortactin, which are actin-associated substrates of Src. RNA interference-induced knockdown of the Ca(2+)-dependent tyrosine kinase, Pyk2, resulted in inhibition of PDGF-induced Src activation and migration. Finally, nifedipine inhibited PDGF-induced Pyk2 activation in a dose-dependent manner.
Conclusion: These data suggest that nifedipine interferes with VSMC migration via inhibition of the Pyk2-Src axis and inhibition of actin remodeling processes, including membrane ruffling and lamellipodium formation.