Muscle Cell Migration via Activation of Phosphatidylinositol 3-Kinase

The steroid hormone 1 ,25-dihydroxyvitamin D3 [1 ,25-(OH)2D3] promotes vascular smooth muscle cell (VSMC) growth and calcification, but the precise mechanism by which 1 ,25-(OH)2D3 regulates VSMC migration is unknown. In rat aortic SMCs, we found that 1 ,25-(OH)2D3 (0.1 to 100 nmol/L) induced a dose-dependent increase in VSMC migration. This response required the activation of phosphatidylinositol 3-kinase (PI3 kinase) because 1 ,25-(OH)2D3–induced migration was completely abolished by the PI3 kinase inhibitors, LY294002 (10 mol/L) or wortmannin (30 nmol/L). Furthermore, the RNA polymerase inhibitor, 5,6-dichlorobenzimidazole riboside (50 mol/L), did not affect 1 ,25-(OH)2D3–induced VSMC migration, suggesting that gene transcription is not involved in this rapid response. Using analogs of 1 ,25-(OH)2D3, which have been characterized for their abilities to induce either transcriptional or nontranscriptional responses of 1 ,25-(OH)2D3, we found that 1 ,25-dihydroxylumisterol, which is a potent agonist of the rapid, nongenomic responses, was equipotent with 1 ,25-(OH)2D3 in inducing PI3 kinase activity and VSMC migration. Moreover, 1 ,25-(OH)2D3, which specifically antagonizes the nongenomic actions of 1 ,25(OH)2D3, abolished 1 ,25-(OH)2D3–induced PI3 kinase activity and VSMC migration, whereas the inhibitor of the genomic actions of vitamin D, (23S)-25-dehydro-1 -OH-D3-26,23-lactone, did not affect these responses. These results indicate that 1 ,25-(OH)2D3 induces VSMC migration independent of gene transcription via PI3 kinase pathway, and suggest a possible mechanism by which 1 ,25-(OH)2D3 may contribute to neointima formation in atherosclerosis and vascular remodeling. (Circ Res. 2002;91:17-24.)