Estudios científicos
Essential role of ER-alpha-dependent NO production in resveratrol-mediated inhibition of restenosis
Abstract:
Resveratrol, a red wine polyphenol, is known to exhibit vascular-protective effects and reduce vascular smooth muscle cell mitogenesis. Vascular smooth muscle cell proliferation is a critical factor in the pathogenesis of restenosis, the re-narrowing of vessels that often occurs after angioplasty and/or stent implantation. Though resveratrol has been shown to be an estrogen receptor (ER) modulator, the role of the ER in resveratrol-mediated protection against restenosis has not yet been elucidated in vivo. Therefore, using a mouse carotid artery injury model, our objective was to determine the role of ER-alpha in modulating resveratrol-mediated effects on neointimal hyperplasia. Female wild-type and estrogen receptor-alpha (-/-) mice were administered a high fat diet +/- resveratrol (RESV) for 2 weeks. A carotid artery endothelial denudation procedure was conducted, and the mice were administered a high fat diet +/- RESV for an additional 2 weeks. RESV treated wild-type mice exhibited a dramatic decrease in restenosis, with an increased arterial nitric oxide synthase (NOS) activity and NO production. However, in the ER-alpha (-/-) mice, RESV failed to afford protection and failed to increase NO production, apparently due to a decreased availability of the NOS co-factor tetrahydrobiopterin. To verify the role of NO in RESV-mediated effects, mice were co-administered RESV plus a non-selective NOS inhibitor, L-NAME. Co-treatment with L-NAME significantly attenuated the anti-restenotic properties of RESV. These data thus suggest that RESV inhibits vascular proliferative responses after injury, predominately through an ER-alpha-dependent increase in NO production.
Comentarios divulgativos:
Del resveratrol se sabe que tiene efectos vasculares y reduce la mitogénesis de las células musculares lisas. La proliferación celular del músculo liso vascular es un factor crítico en la patogénesis de la reestenosis, el re-estrechamiento de los vasos que a menudo se produce después de una angioplastia. Aunque el resveratrol ha demostrado ser un modulador del receptor del estrógeno (ER) el papel del resveratrol en la reestenosis todavía no ha sido aclarado in vivo. Para ello usando un ratón modelo para lesiónes de la arteria carótida se determinó el papel del ER-alfa en la modulación de los efectos mediados por el resveratrol sobre la hiperplasia neointimal. A los ratones se les administró una dieta rica en grasas + / – RESV durante 2 semanas. Para comprobar el papel del NO en los efectos mediados por el RESV a los ratones se les administró conjuntamente RESV más un inhibidor no selectivo de NOS. Este Co- atenuó significativamente las propiedades anti-reestenóticas del RESV. Estos datos sugieren que el RESV inhibe las respuestas proliferativas vasculares después de una lesión, principalmente mediante un aumento de ER-alfa-dependiente de la producción de NO.
