Essential role of ER-α-dependent NO production in resveratrol-mediated inhibition of restenosis

Abstract

veratrol (Resv), 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 renarrowing of vessels that often occurs after angioplasty and/or stent implantation. Although Resv has been shown to be an estrogen receptor (ER) modulator, the role of the ER in Resv-mediated protection against restenosis has not yet been elucidated in vivo. Therefore, with the use of a mouse carotid artery injury model, our objective was to determine the role of ER in modulating Resv-mediated effects on neointimal hyperplasia. Female wild-type and ER-␣ Ϫ/Ϫ mice were administered a high-fat diet Ϯ Resv for 2 wk. A carotid artery endothelial denudation procedure was conducted, and the mice were administered a high-fat diet Ϯ Resv for an additional 2 wk. Resv-treated wild-type mice exhibited a dramatic decrease in restenosis, with an increased arterial nitric oxide (NO) synthase (NOS) activity and NO production. However, in the ER-␣ Ϫ/Ϫ mice, Resv failed to afford protection and failed to increase NO production, apparently because of a decreased availability of the NOS cofactor tetrahydrobiopterin. To verify the role of NO in Resvmediated effects, mice were coadministered Resv plus a nonselective NOS inhibitor, N G -nitro-L-arginine methyl ester (L-NAME). Cotreatment with L-NAME significantly attenuated the antirestenotic properties of Resv. These data thus suggest that Resv inhibits vascular proliferative responses after injury, predominately through an ER-␣-dependent increase in NO production. estrogen receptor; nitric oxide RESTENOSIS, or vessel renarrowing, is a major limiting factor in patients undergoing angioplasty and/or stent implantation (25). The primary cause for restenosis is neointimal formation, characterized by abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) from the media of the vessel wall to the intima (32). Thus the inhibition of VSMC proliferation can potentially inhibit restenosis. Several clinical studies have demonstrated an increased risk for developing cardiovascular disorders in postmenopausal compared with premenopausal women (29). This suggests an important role for estrogen and estrogen receptors (ERs) in the increased incidence of cardiovascular disorders in postmenopausal women. Several rodent studies have assessed the efficacy of 17␤-estradiol, a synthetic estrogen, in inhibiting restenosis. A mechanism by which the ERs modulate vascular function is via an ER-dependent increase in nitric oxide (NO) synthase (NOS) activity and NO production, occurring through both genomic and nongenomic mechanisms (2,8,26).According to the French paradox, epidemiological evidence demonstrating a decreased incidence in cardiovascular disorders among French populations consuming high amounts of saturated fat was associated with a daily consumption of red wine. Resveratrol (Resv) is a red wine polyphenol believed to be a key contribut...

Greater Effectiveness of ε-Viniferin in Red Wine Than Its Monomer Resveratrol for Inhibiting Vascular Smooth Muscle Cell Proliferation and Migration

“…[2][3][4] Epidemiological studies have also shown that red wine consumption was irreversibly correlated to a risk of coronary heart disease. 5) In practice, resveratrol inhibits the oxidation of human low-density lipoproteins, 6,7) platelet aggregation, 8) and the proliferation of vascular smooth muscle cells (VSMCs) [9][10][11][12][13][14] which can prevent the pathogenesis of atherosclerosis. Resveratrol is therefore believed to be a strong candidate for explaining the ''French paradox'' that indicates the reduction in coronary heart disease observed with red wine drinkers.…”

The pharmacology of resveratrol in animals and humans

“…In earlier studies, RSV treatment was shown to attenuate restenosis [140][141][142] with reduced neointimal hyperplasia [140][141][142][143][144] in artery injury models of rabbits [140], rats [141,143,144] and mice [142]. In addition, RSV upregulated the expression of eNOS [141][142][143], p-eNOS [143], NO [142], Sirt1 [143], p-AMPK [143] while it downregulated that of iNOS [143], platelet endothelial cell adhesion molecule (PECAM) [143], MMP-9 [143], 8-iso-PGF2α [144], MCP-1 [144], and IL-6 [144]. More recently, it has been found RSV treatment prevented restenosis with a reduction of neointimal hyperplasia in carotid artery-injured [142][143][144] and femoral wire-injured [143] models with rodents.…”

“…In addition, RSV upregulated the expression of eNOS [141][142][143], p-eNOS [143], NO [142], Sirt1 [143], p-AMPK [143] while it downregulated that of iNOS [143], platelet endothelial cell adhesion molecule (PECAM) [143], MMP-9 [143], 8-iso-PGF2α [144], MCP-1 [144], and IL-6 [144]. More recently, it has been found RSV treatment prevented restenosis with a reduction of neointimal hyperplasia in carotid artery-injured [142][143][144] and femoral wire-injured [143] models with rodents. The suppressive activity of RSV on neointimal hyperplasia was abolished in ER-α -/-mice [142], endothelial NOS (eNOS) knockout mice [143], and in N G -nitro-L-arginine methyl ester (L-NAME)-co-treated mice [142] or rats [143], suggesting that RSV exerts the effect through ER-α-dependent NO production [142].…”

“…More recently, it has been found RSV treatment prevented restenosis with a reduction of neointimal hyperplasia in carotid artery-injured [142][143][144] and femoral wire-injured [143] models with rodents. The suppressive activity of RSV on neointimal hyperplasia was abolished in ER-α -/-mice [142], endothelial NOS (eNOS) knockout mice [143], and in N G -nitro-L-arginine methyl ester (L-NAME)-co-treated mice [142] or rats [143], suggesting that RSV exerts the effect through ER-α-dependent NO production [142].…”

“…With clinical signs of the protective effect of RSV on restenosis, RSV induced arterial NOS activity and NO production in carotid artery injured mice with high-fat diet [142], and reduced inflammatory mediators…”