Published Online
on July 24, 2006

A more recent version of this article appeared on September 1, 2006

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Submitted on February 10, 2006
Revised on February 28, 2006

Tumor Necrosis Factor- and Vascular Angiotensin II in Estrogen-Deficient Rats

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

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

^* To whom correspondence should be addressed. E-mail: sandra.davidge{at}ualberta.ca.

Abstract--Alterations in the vascular angiotensin II system may play a role in the pathophysiology of vascular disease after menopause. In previous studies we have shown that an increase in tumor necrosis factor (TNF)- levels in aging rats because of estrogen deficiency may result in vascular dysfunction. In this study we investigated the effect of TNF- inhibition in angiotensin II modulation of vascular function in aging female animals. Female rats approaching reproductive senescence (12 to 15 months old) were ovariectomized and treated with placebo, estrogen, or a selective TNF- inhibitor (etanercept) for 4 weeks. Expression of angiotensin II in mesenteric arteries was evaluated by immunofluorescence, and the expression of angiotensin-converting enzyme and angiotensin type I receptor (AT₁R) was investigated by Western immunoblot. Vascular function was assessed in mesenteric arteries using the myograph system, and the role of endogenous angiotensin II on adrenergic vasoconstriction was evaluated in vitro by selective AT₁R blockade (Candesartan; 10 µmol/L). Our data demonstrate that estrogen-depleted rats have higher serum levels of TNF- and greater sensitivity to phenylephrine vasoconstriction compared with estrogen-replaced animals, which was attenuated by AT₁R blockade. In vivo TNF- inhibition or estrogen replacement reduced phenylephrine constriction of mesenteric arteries and decreased the modulation of this vasoconstriction by candesartan. These functional changes were accompanied by a reduction in the vascular expression of angiotensin II, angiotensin-converting enzyme, and AT₁R. These observations indicate that upregulation of TNF- during estrogen deficiency may contribute to enhance vascular constriction by altering the vascular angiotensin II system.

Key words: tumor necrosis factor • aging • estrogen • vasoconstriction • angiotensin II

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