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Tumor necrosis factor-alpha (TNF-alpha) is involved in the pathogenesis of vascular disease. Clinical studies have shown that postmenopausal women have higher serum TNF-alpha levels; however, whether this increase in TNF-alpha is associated with vascular dysfunction is unknown. We investigated whether estrogen deficiency is associated with increased serum TNF-alpha levels and tested the effects of in vivo TNF-alpha inhibition on vascular reactivity. Aged (12 to 15 months) Sprague-Dawley rats were ovariectomized and treated with placebo, estrogen, or a TNF-alpha inhibitor (Etanercept; 0.3 mg/kg) for 4 weeks. Serum TNF-alpha was determined by a bioassay, and vascular function was evaluated in the myograph system. Estrogen-deficient animals had higher serum levels of TNF-alpha compared with either estrogen-replaced animals or animals treated with Etanercept. Moreover, in estrogen-deficient rats, TNF-alpha 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-alpha 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-alpha levels compared with estrogen-replaced animals. Moreover, a decrease in serum bioactive TNF-alpha by a soluble TNF-alpha receptor (Etanercept) results in increased modulation of vascular function by NO. These observations suggest that TNF-alpha could be a mediator of vascular dysfunction associated with estrogen deficiency.
Arenas et al. (Tue,) studied this question.