Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 308, Issue 7, Pages H723-H732Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00681.2014
Keywords
testosterone; estrogen; endothelium; ROS; angiotensin II; NADPH oxidase; cardiovascular disease; hypoactive sexual desire disorder
Funding
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES/DGU) [269/12]
- FAPESP [2010/03608-1]
- Ministerio de Economia y Competitividad, Instituto de Salud Carlos III\ [RIC RD12/0042/0006]
- Programa Hispano-Brasileno de Cooperacion Interuniversitaria [HBP-2011-0054 PC]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [10/03608-1] Funding Source: FAPESP
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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).
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