title: Association of testosterone with estrogen abolishes the beneficial effects of estrogen treatment by increasing ROS generation in aorta endothelial cells.
abstract: Testosterone has been added to hormone replacement therapy to treat sexual dysfunction in postmenopausal women. Whereas estrogen has been associated with vascular protection, the vascular effects of testosterone are contradictory and the effects of its association with estrogen are largely unknown. In this study we determined the effects of testosterone associated with conjugated equine estrogen (CEE) on vascular function using a model of hypertensive postmenopausal female: ovariectomized spontaneously hypertensive rats. Female spontaneously hypertensive rats were divided into sham-operated, ovariectomized (OVX), and OVX treated for 15 days with either CEE alone (OVX+CEE) or associated with testosterone (OVX+CEE+T). Angiotensin II (ANG II)-induced contraction was markedly increased in aortic rings from OVX compared with sham-operated rats. CEE treatment restored ANG-II responses, a beneficial effect abrogated with CEE+T. CEE treatment also increased endothelium-dependent relaxation, which was impaired in OVX rats. This effect was lost by CEE+T. Treatment of aortas with losartan (ANG-II type-1 receptor antagonist) or apocynin (NADPH-oxidase inhibitor) restored the endothelium-dependent relaxation in OVX and CEE+T, establishing an interplay between ANG-II and endothelial dysfunction in OVX and CEE+T. The benefits by CEE were associated with downregulation of NADPH-oxidase subunits mRNA expression and decreased reactive oxygen species generation. The association of testosterone with CEE impairs the benefits of estrogen on OVX-associated endothelial dysfunction and reactive oxygen species generation in rat aorta by a mechanism that involves phosphorylation of the cytosolic NADPH-oxidase subunit p47(phox).
authors: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil;
authors: Tiago J
authors: TJ
authors: Costa
authors: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil; Department of Physiological Sciences, State University of Londrina, Londrina, Brazil;
authors: Graziela S
authors: GS
authors: Ceravolo
authors: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil;
authors: Rosangela A
authors: RA
authors: dos Santos
authors: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil;
authors: Maria Aparecida
authors: MA
authors: de Oliveira
authors: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil;
authors: Priscila X
authors: PX
authors: Araújo
authors: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil;
authors: Luciana R
authors: LR
authors: Giaquinto
authors: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Brazil; and.
authors: Rita C
authors: RC
authors: Tostes
authors: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil;
authors: Eliana H
authors: EH
authors: Akamine
authors: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil;
authors: Zuleica B
authors: ZB
authors: Fortes
authors: Group of Atherosclerosis and Coronary disease, Institut Clinic del Torax, Institut d'Investigaciones Biomédiques August Pi I Sunyer, Barcelona, Spain.
authors: Ana Paula
authors: AP
authors: Dantas
authors: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil; mhcarval@icb.usp.br.
authors: Maria Helena C
authors: MH
authors: Carvalho
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D005260:Female; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D011918:Rats, Inbred SHR; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D004791:Enzyme Inhibitors; D004966:Estrogens, Conjugated (USP); D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D013739:Testosterone; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1
keywords: NADPH oxidase; ROS; angiotensin II; cardiovascular disease; endothelium; estrogen; hypoactive sexual desire disorder; testosterone