title: Tumor necrosis factor-alpha and vascular angiotensin II in estrogen-deficient rats.
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)-alpha levels in aging rats because of estrogen deficiency may result in vascular dysfunction. In this study we investigated the effect of TNF-alpha 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-alpha 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 (AT(1)R) 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 AT(1)R blockade (Candesartan; 10 micromol/L). Our data demonstrate that estrogen-depleted rats have higher serum levels of TNF-alpha and greater sensitivity to phenylephrine vasoconstriction compared with estrogen-replaced animals, which was attenuated by AT(1)R blockade. In vivo TNF-alpha 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 AT(1)R. These observations indicate that upregulation of TNF-alpha during estrogen deficiency may contribute to enhance vascular constriction by altering the vascular angiotensin II system.
authors.affiliation: Perinatal Research Centre, Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Arenas
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Armstrong
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D004730:Endothelium, Vascular / Q000502:physiology; D004967:Estrogens / Q000172:deficiency*; D000068800:Etanercept; D005260:Female; D007074:Immunoglobulin G / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D013777:Tetrazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004967:Estrogens; D007074:Immunoglobulin G; D044140:Receptor, Angiotensin, Type 1; D018124:Receptors, Tumor Necrosis Factor; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; D007703:Peptidyl-Dipeptidase A; D000068800:Etanercept; C081643:candesartan