Nifedipine interferes with migration of vascular smooth muscle cells via inhibition of Pyk2-Src axis.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Soe
Nwe Nwe
NN
Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
Ishida
Takafumi
T
Ishida
Mari
M
Sawano
Mariko
M
Abe
Keiko
K
Miho
Narimasa
N
Chayama
Kazuaki
K
Kihara
Yasuki
Y
Yoshizumi
Masao
M
D000199:Actins / Q000378:metabolism; D002121:Calcium Channel Blockers; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D011554:Pseudopodia / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000199:Actins; D002121:Calcium Channel Blockers; D010982:Platelet-Derived Growth Factor; D051418:Focal Adhesion Kinase 2; D019061:src-Family Kinases; D009543:Nifedipine