Chronic Tumor Necrosis Factor-α Inhibition Enhances NO Modulation of Vascular Function in Estrogen-Deficient Rats
- 1 July 2005
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hypertension
- Vol. 46 (1), 76-81
- https://doi.org/10.1161/01.hyp.0000168925.98963.ef
Abstract
Tumor necrosis factor-α (TNF-α) is involved in the pathogenesis of vascular disease. Clinical studies have shown that postmenopausal women have higher serum TNF-α levels; however, whether this increase in TNF-α is associated with vascular dysfunction is unknown. We investigated whether estrogen deficiency is associated with increased serum TNF-α levels and tested the effects of in vivo TNF-α inhibition on vascular reactivity. Aged (12 to 15 months) Sprague-Dawley rats were ovariectomized and treated with placebo, estrogen, or a TNF-α inhibitor (Etanercept; 0.3 mg/kg) for 4 weeks. Serum TNF-α was determined by a bioassay, and vascular function was evaluated in the myograph system. Estrogen-deficient animals had higher serum levels of TNF-α compared with either estrogen-replaced animals or animals treated with Etanercept. Moreover, in estrogen-deficient rats, TNF-α 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-α 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-α levels compared with estrogen-replaced animals. Moreover, a decrease in serum bioactive TNF-α by a soluble TNF-α receptor (Etanercept) results in increased modulation of vascular function by NO. These observations suggest that TNF-α could be a mediator of vascular dysfunction associated with estrogen deficiency.Keywords
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