In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 91, No. 1 ( 2002-07-12), p. 17-24
Abstract:
The steroid hormone 1α,25-dihydroxyvitamin D 3 [1α, 25-(OH) 2 D 3 ] promotes vascular smooth muscle cell (VSMC) growth and calcification, but the precise mechanism by which 1α, 25-(OH) 2 D 3 regulates VSMC migration is unknown. In rat aortic SMCs, we found that 1α, 25-(OH) 2 D 3 (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 1α, 25-(OH) 2 D 3 -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 1α, 25-(OH) 2 D 3 -induced VSMC migration, suggesting that gene transcription is not involved in this rapid response. Using analogs of 1α, 25-(OH) 2 D 3 , which have been characterized for their abilities to induce either transcriptional or nontranscriptional responses of 1α, 25-(OH) 2 D 3 , we found that 1α,25-dihydroxylumisterol, which is a potent agonist of the rapid, nongenomic responses, was equipotent with 1α, 25-(OH) 2 D 3 in inducing PI3 kinase activity and VSMC migration. Moreover, 1β, 25-(OH) 2 D 3 , which specifically antagonizes the nongenomic actions of 1α, 25-(OH) 2 D 3 , abolished 1α, 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-1α-OH-D 3 -26,23-lactone, did not affect these responses. These results indicate that 1α, 25-(OH) 2 D 3 induces VSMC migration independent of gene transcription via PI3 kinase pathway, and suggest a possible mechanism by which 1α, 25-(OH) 2 D 3 may contribute to neointima formation in atherosclerosis and vascular remodeling.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/01.RES.0000025269.60668.0F
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2002
detail.hit.zdb_id:
1467838-X
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