Resveratrol Improved Flow-Mediated Outward Arterial Remodeling in Ovariectomized Rats with Hypertrophic Effect at High Dose

Abstract

ObjectivesChronic increases in blood flow in resistance arteries induce outward remodeling associated with increased wall thickness and endothelium-mediated dilatation. This remodeling is essential for collateral arteries growth following occlusion of a large artery. As estrogens have a major role in this remodeling, we hypothesized that resveratrol, described as possessing phytoestrogen properties, could improve remodeling in ovariectomized rats.MethodsBlood flow was increased in vivo in mesenteric arteries after ligation of adjacent arteries in 3-month old ovariectomized rats treated with resveratrol (5 or 37.5 mg/kg per day: RESV5 or RESV37.5) or vehicle. After 2 weeks arterial structure and function were measured in vitro in high flow (HF) and normal flow (NF) arteries isolated from each rat.ResultsArterial diameter was greater in HF than in NF arteries in ovariectomized rats treated with RESV5 or RESV37.5, not in vehicle-treated rats. In mice lacking estrogen receptor alpha diameter was equivalent in HF and NF arteries whereas in mice treated with RESV5 diameter was greater in HF than in NF vessels. A compensatory increase in wall thickness and a greater phenylephrine-mediated contraction were observed in HF arteries. This was more pronounced in HF arteries from RESV37.5-treated rats. ERK1/2 phosphorylation, involved in hypertrophy and contraction, were higher in RESV37.5-treated rats than in RESV5- and vehicle-treated rats. Endothelium-dependent relaxation was greater in HF than in NF arteries in RESV5-treated rats only. In HF arteries from RESV37.5-treated rats relaxation was increased by superoxide reduction and markers of oxidative stress (p67phox, GP91phox) were higher than in the 2 other groups.ConclusionResveratrol improved flow-mediated outward remodeling in ovariectomized rats thus providing a potential therapeutic tool in menopause-associated ischemic disorders. This effect seems independent of the estrogen receptor alpha. Nevertheless, caution should be taken with high doses inducing excessive contractility and hypertrophy in association with oxidative stress in HF arteries.

Membrane estrogen receptor alpha (ERα) participates in flow-mediated dilation in a ligand-independent manner

“…This remodeling involves an early inflammatory phase allowing cell growth and reorganization in the arterial wall ( Caillon et al, 2016 ) and a dilatory phase involving NO, prostaglandins and CO production ( Dumont et al, 2007 ; Belin de Chantemèle et al, 2010 ; Freidja et al, 2011 ). Noteworthy, flow-mediated remodeling is absent in ovariectomized rats and mice and in Esr1 -/- mice ( Tarhouni et al, 2013 ) whereas this remodeling is preserved in ovariectomized rats treated with E2 ( Tarhouni et al, 2014b ) or resveratrol ( Petit et al, 2016 ). More recently, we have shown that this remodeling requires activation of AF2 and is independent on membrane-located ERα ( Guivarc’h et al, 2018 ).…”

Resveratrol and the Interaction between Gut Microbiota and Arterial Remodelling

“…Resveratrol has been shown to prevent arterial remodelling and stiffening in both animal and clinical studies. In rats, both low-dose and high-dose resveratrol treatments improve flow-mediated outward remodelling [80]. A long-term low-dose dietary resveratrol supplement reduces arterial stiffness (measured by the aortic pulse wave velocity) in rats [81].…”

Coadjuvants in the Diabetic Complications: Nutraceuticals and Drugs with Pleiotropic Effects

“…For that reason, this potent molecule (even with a short half-life) also would be highly beneficial as an adjuvant therapy for diabetes. Additionally, under in vitro [ 107 , 108 ] and in vivo [ 109 , 110 , 111 ] experimental conditions that mimic human diabetes, resveratrol has been shown to have a potential benefit in several multi-target mechanisms for diabetic complications, as presented below.…”