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

Abstract

Abstract-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 Ⅲ nitric oxide Ⅲ tumor necrosis factor Ⅲ estrogen Ⅲ vascular function C ardiovascular disease is the leading cause of death for women in developed countries. Although menopause is considered a major risk factor for vascular disease, the pathophysiological mechanisms linking the decrease in ovarian hormones that occurs in menopause with alterations in vascular function are still unclear.NO is an important vasodilator and has an important role in the control of vascular homeostasis, including its ability to modulate the actions of vasoconstrictors such as the ␣-1-adrenergic agonist phenylephrine (PE). 1 In fact, a decrease in NO modulation of vascular function is associated with higher risk of developing vascular disease. 2 Animal and human studies have shown that the decline of the ovarian function is associated with decreased NO. [3][4][5] Although the mechanisms remain unknown, the decrease in bioavailable NO seems to be attributable to a decrease in its production or enhanced inactivation by superoxide anion that results in formation of peroxynitrite.Tumor necrosis factor-␣ (TNF-␣) is a proinflammatory cytokine proposed to be involved in the pathogenesis of vascular...

Age-associated impairment in vasorelaxation to fluid shear stress in the female vasculature is improved by TNF-α antagonism

“…Thus etanercept binds and inactivates circulating TNF-␣. The etanercept dose was calculated based on effective TNF-␣ inhibition from previous studies in humans and rats (15,16), including our own studies in this model (1,4). Rats were euthanized by exsanguination while under anesthesia (pentobarbital sodium, ϳ60 mg/kg body wt).…”

“…Inflammatory factors are involved in the pathogenesis of vascular disorders, and some evidence suggests that cytokines may mediate some of the vascular changes associated with aging. Indeed, we recently reported that in female rats, aging is associated with an increase in the levels of TNF-␣, a proinflammatory cytokine, which results in alterations of vascular function (1).…”

Estrogen is a modulator of vascular inflammation

“…Estrogen deficiency has been shown to upregulate TNFa levels in aged animals with deleterious effects on vascular function. Such effects are largely mediated through increased oxidative stress and can be reversed through exogenous estrogen, a TNFa inhibitor or antioxidants (19). Estrogen supplementation also reduces TNFa levels in cells of monocyte/macrophage lineage through involving the non-ERE transcription factor AP-1.…”

Sex-dependent hepatic transcripts and metabolites in the development of glucose intolerance and insulin resistance in Zucker diabetic fatty rats

“…No single risk factor or combination of factors has yet been shown to fully explain this, but the fact that risk protection disappears after menopause strongly suggests that female hormones play a protective role. Oestrogens exert many physiological effects that might influence both cardiovascular risk and insulin resistance, including antiinflammatory (Arenas et al 2005) and antioxidant (Louet et al 2004, Baba et al 2005, Borrás et al 2005 properties. Oestrogens have also been shown to inhibit lipogenesis and stimulate lipolysis in abdominal visceral fat depots, to promote use of lipid as a fuel by muscle (D'Eon et al 2005) and reduce central adiposity (Perrone et al 1999).…”