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(Circulation Research. 2002;91:17.)
© 2002 American Heart Association, Inc.

Molecular Medicine

1,25-Dihydroxyvitamin D₃ Induces Vascular Smooth Muscle Cell Migration via Activation of Phosphatidylinositol 3-Kinase

Michela C. Rebsamen, Jianxin Sun, Anthony W. Norman, James K. Liao

From Vascular Medicine Research (M.C.R., J.S., J.K.L.), Brigham and Women’s Hospital and Harvard Medical School, Cambridge, Mass; and the Department of Biochemistry and the Division of Biomedical Sciences (A.W.N.), University of California, Riverside, Calif.

Correspondence to James K. Liao, MD, Vascular Medicine Research, Brigham & Women’s Hospital, 65 Landsdowne St, Room 275, Cambridge, MA 02139. E-mail jliao{at}rics.bwh.harvard.edu

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 µmol/L) or wortmannin (30 nmol/L). Furthermore, the RNA polymerase inhibitor, 5,6-dichlorobenzimidazole riboside (50 µmol/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, 1ß, 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.

Key Words: steroid hormones • smooth muscle • migration • phosphatidylinositol 3-kinase

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