Tumor necrosis factor-α inhibition improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women

Objective: Tumor necrosis factor (TNF)-alpha, a pleiotropic pro-inflammatory cytokine involved in a variety of biological processes including oxidative stress, has been associated with vascular dysfunction in aged and ovariectomized animals. We determined whether acute inhibition of TNF-alpha improves vascular endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women. Methods: Arterial stiffness (carotid artery compliance) and endothelial function (brachial artery flow-mediated dilation [FMD]) were measured in postmenopausal women (n = 23; 57 +/- 1 years, mean +/- SE) before and following randomization to two days of either transdermal estradiol (0.05 mg/d, N = 12) or placebo (N = 11) alone and following a single subcutaneous injection of the TNF-alpha inhibitor, etanercept (25 mg), and in premenopausal (n = 9; 33 +/- 2 years) before and following etanercept. Results and conclusions: Baseline carotid artery compliance and brachial artery FMD were lower in postmenopausal than premenopausal women (P < 0.0001). In postmenopausal women, carotid artery compliance (n = 12; 0.59 +/- 0.05-0.78 +/- 0.06 mm(2)/mmHg x 10(-1), P < 0.001) and FMD (4.1 +/- 0.6 -6.0 +/- 0.7%, P = 0.02) increased in response to estradiol but not placebo (n = 11). Carotid artery compliance (0.71 +/- 0.06-0.81 +/- 0.06 mm(2)/mmHg x 10(-1), P = 0.02) and FMD (5.2 +/- 0.7-7.5 +/- 0.9%, P = 0.003) increased with etanercept in the placebo group but had no effect in postmenopausal randomized to estradiol or premenopausal women. These results suggest that TNF-alpha contributes to impaired endothelial-dependent vasodilation and arterial stiffening in estrogen-deficient postmenopausal women. (C) 2013 Elsevier Ireland Ltd. All rights reserved.