Age-associated impairment in vasorelaxation to fluid shear stress in the female vasculature is improved by TNF-alpha antagonism.
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-alpha. Thus we investigated the role of in vivo TNF-alpha inhibition on vascular responses to shear stress in aging female rats. Mesenteric arteries (approximately 150 microm) were isolated from young (3 mo) and ovariectomized Sprague-Dawley female rats approaching reproductive senescence (12 mo) treated with either placebo or a TNF-alpha 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 approximately 70% of their initial diameter. Perfusate flow was increased in steps from 0 to 150 microl/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-alpha 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-alpha inhibition improves flow-mediated arterial dilation in resistance arteries of aged female animals.
Arenas
Ivan A
IA
Perinatal Research Centre, Department of Obstetrics and Gynecology, 220 HMRC, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Xu
Yi
Y
Davidge
Sandra T
ST
D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D000068800:Etanercept; D005260:Female; D007074:Immunoglobulin G / Q000494:pharmacology*; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor; D012737:Sex Factors; D033081:Shear Strength; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000068800:Etanercept