Age-associated impairment in vasorelaxation to fluid shear stress in the female vasculature is improved by TNF-α antagonism

Abstract

Aging is associated with alterations in vascular homeostasis, including a reduction in flow-mediated vasodilation, which in women is related to the onset of menopause. We previously found that in female animals, aging is associated with an increase in TNF-α. Thus we investigated the role of in vivo TNF-α inhibition on vascular responses to shear stress in aging female rats. Mesenteric arteries (∼150 μm) were isolated from young (3 mo) and ovariectomized Sprague-Dawley female rats approaching reproductive senescence (12 mo) treated with either placebo or a TNF-α inhibitor (etanercept; 0.3 mg/kg) and were mounted on a pressure myograph system. Vessels were equilibrated at an intraluminal pressure of 60 mmHg and then preconstricted with phenylephrine at ∼70% of their initial diameter. Perfusate flow was increased in steps from 0 to 150 μl/min. Compared with young vessels, aged vessels have a decrease in flow-mediated dilation [maximal dilation (means ± SE): 52 ± 4 vs. 24 ± 15%; P < 0.05], which was improved by TNF-α inhibition. Moreover, in aged vessels maximal dilation to flow was achieved at higher levels of shear stress compared with young vessels. In all groups, flow-mediated dilation was abolished by either endothelial removal or nitric oxide synthase inhibition with NG-nitro-l-arginine methyl ester. However, the modulation by NG-nitro-l-arginine methyl ester was reduced in vessels from aged animals compared with young animals but was improved in the etanercept-treated aged animals. In vivo chronic TNF-α inhibition improves flow-mediated arterial dilation in resistance arteries of aged female animals.