1alpha,25-dihydroxyvitamin D3 induces vascular smooth muscle cell migration via activation of phosphatidylinositol 3-kinase.
The steroid hormone 1alpha,25-dihydroxyvitamin D3 [1alpha, 25-(OH)2D3] promotes vascular smooth muscle cell (VSMC) growth and calcification, but the precise mechanism by which 1alpha, 25-(OH)2D3 regulates VSMC migration is unknown. In rat aortic SMCs, we found that 1alpha, 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 1alpha, 25-(OH)2D3-induced migration was completely abolished by the PI3 kinase inhibitors, LY294002 (10 micromol/L) or wortmannin (30 nmol/L). Furthermore, the RNA polymerase inhibitor, 5,6-dichlorobenzimidazole riboside (50 micromol/L), did not affect 1alpha, 25-(OH)2D3-induced VSMC migration, suggesting that gene transcription is not involved in this rapid response. Using analogs of 1alpha, 25-(OH)2D3, which have been characterized for their abilities to induce either transcriptional or nontranscriptional responses of 1alpha, 25-(OH)2D3, we found that 1alpha,25-dihydroxylumisterol, which is a potent agonist of the rapid, nongenomic responses, was equipotent with 1alpha, 25-(OH)2D3 in inducing PI3 kinase activity and VSMC migration. Moreover, 1beta, 25-(OH)2D3, which specifically antagonizes the nongenomic actions of 1alpha, 25-(OH)2D3, abolished 1alpha, 25-(OH)2D3-induced PI3 kinase activity and VSMC migration, whereas the inhibitor of the genomic actions of vitamin D, (23S)-25-dehydro-1alpha-OH-D3-26,23-lactone, did not affect these responses. These results indicate that 1alpha, 25-(OH)2D3 induces VSMC migration independent of gene transcription via PI3 kinase pathway, and suggest a possible mechanism by which 1alpha, 25-(OH)2D3 may contribute to neointima formation in atherosclerosis and vascular remodeling.
Vascular Medicine Research, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Mass 02139, USA.
Michela C
MC
Rebsamen
Jianxin
J
Sun
Anthony W
AW
Norman
James K
JK
Liao
D000818:Animals; D015153:Blotting, Western; D002117:Calcitriol / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053495:Osteopontin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000187:drug effects
C121609:1,25-dihydroxylumisterol(3); D004791:Enzyme Inhibitors; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; D004004:Dichlororibofuranosylbenzimidazole; D019869:Phosphatidylinositol 3-Kinases; D012319:RNA Polymerase II; D002117:Calcitriol; D004875:Ergosterol