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(Hypertension. 2005;46:76.)
© 2005 American Heart Association, Inc.

Original Articles

Chronic Tumor Necrosis Factor- Inhibition Enhances NO Modulation of Vascular Function in Estrogen-Deficient Rats

Ivan A. Arenas; Stephen J. Armstrong; Yi Xu; Sandra T. Davidge

From the Perinatal Research Center, Departments of Obstetrics/Gynecology and Physiology, University of Alberta, Edmonton, Canada.

Correspondence to Sandra T. Davidge, PhD, Perinatal Research Center, 220 HMRC, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. E-mail sandra.davidge{at}ualberta.ca

Tumor necrosis factor- (TNF-) is involved in the pathogenesis of vascular disease. Clinical studies have shown that postmenopausal women have higher serum TNF- levels; however, whether this increase in TNF- is associated with vascular dysfunction is unknown. We investigated whether estrogen deficiency is associated with increased serum TNF- levels and tested the effects of in vivo TNF- inhibition on vascular reactivity. Aged (12 to 15 months) Sprague-Dawley rats were ovariectomized and treated with placebo, estrogen, or a TNF- inhibitor (Etanercept; 0.3 mg/kg) for 4 weeks. Serum TNF- was determined by a bioassay, and vascular function was evaluated in the myograph system. Estrogen-deficient animals had higher serum levels of TNF- compared with either estrogen-replaced animals or animals treated with Etanercept. Moreover, in estrogen-deficient rats, TNF- inhibition reduced the constriction of mesenteric arteries to phenylephrine, increased the modulation of this vasoconstriction by the NO synthase inhibitor nitro-L-arginine methyl ester, and decreased the modulation by a superoxide scavenger (Mn(III)tetrakis(4-benzoic acid) porphyrin chloride). Furthermore, endothelium-dependent relaxation was also enhanced by TNF- antagonism. Additionally, vascular expression of endothelial NO synthase was increased in animals treated with Etanercept, whereas the expression of NAD(P)H oxidase gp91phox and p22phox subunits was decreased. These data show that estrogen-deficient female rats have higher bioactive serum TNF- levels compared with estrogen-replaced animals. Moreover, a decrease in serum bioactive TNF- by a soluble TNF- receptor (Etanercept) results in increased modulation of vascular function by NO. These observations suggest that TNF- could be a mediator of vascular dysfunction associated with estrogen deficiency.

Key Words: aging • nitric oxide • tumor necrosis factor • estrogen • vascular function

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Estrogen Regulation of Tumor Necrosis Factor-: A Missing Link Between Menopause and Cardiovascular Risk in Women?

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