1α,25-dihydroxyvitamin D3 induces vascular smooth muscle cell migration via activation of phosphatidylinositol 3-kinase

steroid hormone 1alpha,25-dihydroxyvitamin D-3 [1alpha,25-(OH)(2)D-3] promotes vascular smooth muscle cell (VSMC) growth and calcification, but the precise mechanism by which 1alpha,25-(OH)(2)D-3 regulates VSMC migration is unknown. In rat aortic SMCs, we found that 1alpha,25-(OH)(2)D-3 (OH to 100 nmol/L) induced a dose-dependent increase in VSMC migration. This response required the activation of phosphatidylinositol 3-kinase (PI3 kinase) because 1alpha,25-(OH)(2)D-3-induced migration was completely abolished by the PI3 kinase inhibitors, LY294002 (10 mumol/L) or wortmannin (30 nmol/L). Furthermore, the RNA polymerase inhibitor, 5,6-dichlorobenzimidazole riboside (50 mumol/L), did not affect 1alpha,25-(OH)(2)D-3-induced VSMC migration, suggesting that gene transcription is not involved in this rapid response. Using analogs of 1alpha,25-(OH)(2)D-3, which have been characterized for their abilities to induce either transcriptional or nontranscriptional responses of 1alpha,25-(OH)(2)D-3, we found that 1alpha,25-dihydroxylumisterol, which is a potent agonist of the rapid, nongenomic responses, was equipotent with la,25-(OH)2D3 in inducing PI3 kinase activity and VSMC migration. Moreover, 10,25-(OH)(2)D-3, which specifically antagonizes the nongenomic actions of 1alpha,D-3-induced (OH)(2)D-3, abolished 1alpha,25-(OH)(2)D-3-induced PI3 kinase activity and VSMC migration, whereas the inhibitor of the genomic actions of vitamin D, (23S)-25-dehydro-1alpha-OH-D-3-26,23-lactone, did not affect these responses. These results indicate that 1alpha25-(OH)(2)D-3, induces VSMC migration independent of gene transcription via PI3 kinase pathway, and suggest a possible mechanism by which 1alpha,25-(OH)(2)D-3 may contribute to neointima formation in atherosclerosis and vascular remodeling.