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

Perinatal Research Centre, Departments of Obstetrics and Gynecology and of Physiology, University of Alberta, Edmonton, Alberta, Canada

Submitted 16 September 2005 ; accepted in final form 1 November 2005

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-. Thus we investigated the role of in vivo TNF- 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- 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- 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 N^G-nitro-L-arginine methyl ester. However, the modulation by N^G-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- inhibition improves flow-mediated arterial dilation in resistance arteries of aged female animals.

tumor necrosis factor-; estrogen deficiency; flow dilation; nitric oxide; endothelium

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