Alterações vasculares e a participação do eixo ang- (1/7)/receptor mas em aorta de camundongos fêmeas ovariectomizadas

Abstract

Previous studies have shown that estrogens exert important vasculoprotective effects on both women and laboratory animals. In basic research, the experimental model of ovariectomy in rodents has been effective in reducing estrogen levels, and to further evaluate vascular alterations. Previous studies have shown that ovariectomy can promote vascular remodeling, alter vascular function and modulate certain components from the renin angiotensin system (RAS), highlighting the axis angiotensin- (1-7) [Ang-(1-7)] and Mas receptor. However, little is known about the effect of ovariectomy on the vascular Ang-(1-7)/Mas receptor axis. In addition, in the actual literature, there are several discrepancies regarding the vascular alterations induced by ovariectomy due to the variety of post-surgery time period, animal species and heterogeneity of vascular responses among distinct vascular beds. Thus, in the present study we evaluated vascular changes and the involvement of the Ang-(1-7)/ Mas receptor axis in the aorta of female mice after two weeks of ovariectomy. For this purpose, female C57BL/6 mice were used, weighing on average 20 g and 10-12 weeks aged. The animals were divided into sham (false operated) and OVX (bilateral ovarian removal) groups. After 2 weeks, the animals were sacrificed and, thoracic and abdominal aorta were collected for experiments (CEUA 365/2017). Our results demonstrated that two weeks of ovariectomy drastically reduce the uterine weight of the animals, evidencing the efficacy of the surgery. In our model, ovariectomy did not alter endothelium-dependent and -independent vasodilation, neither contractile responses to phenylephrine (phenyl), nor structural changes in the thoracic aorta of animals. In contrast, it was observed that potassium chloride (KCl)-induced vascular contraction increases after ovarian removal. Moreover, our data showed that Ang-(1-7) decreases the maximum contractile response to phenyl in thoracic aorta segments from Sham animals, and this effect was abolished when nitric oxide (NO) synthase was inhibited or when animals were submitted ovariectomy. We showed that in situ basal production of NO was not altered between the groups, however, after Ang-(1-7) stimulation, NO production was lower in the aortic segments of OVX animals when compared to Sham. Protein analysis of the receptor Mas revealed that the vascular expression of the receptor is decreased after ovariectomy. In addition, although we did not observe changes in reactive oxygen species (ROS) production between the groups, ovariectomy decreased protein expression of certain enzymes associated to redox balance. In summary, our work showed that two weeks of ovariectomy does not promote changes in endothelial-dependent vasorelaxation, neither alter structural parameters in the thoracic aorta of female mice. However, removal of ovaries lead to changes in the Ang-(1-7)/Mas receptor axis, inhibiting the action of the peptide in decreasing the maximum contractile response to phenyl, as a consequence to the decreased Mas receptor expression and reduced vascular NO production in response to Ang-(1-7) stimulation in OVX animal. Altogether, our results suggest a possible estrogenic modulation of Ang-(1-7)/Mas receptor that precedes endothelial dysfunction.