Efeitos da deleção genética dos genes que codificam ECA2 e o receptor mas na evoluçãoda gravdez em camndongos.

Abstract

BACKGROUND: Pregnancy is characterized by an increase in many of the different components of the circulating renin-angiotensin system (RAS). During normal gestation, pregnant woman are normotensive because there is an increased activity of RAS. This could be due, at least in part, to the increased activity of the ACE2/Ang-(1-7)/Mas axis, the vasodilator arm of the RAS. However, it is not clear if the deficiency in this vasodilator axis is a consequence or contributing factor in the development of abnormalities in pregnancy. AIM: The aim of this study was to evaluate the effect of genetic deletion of MAS receptor or ACE2 in the RAS activity and in the hemodynamic changes present in the evolution of regnancy in mice. MATERIALS AND METHODS: To directly investigate this possibility the phenotypic alterations induced by ACE2 or MAS deficiency in C57Bl/6 and FVB/N were determined in pregnant mice. Twelve - twenty weeks old C57Bl/6 ACE2-/-, C57Bl/6 MAS-/-, FVB/N MAS-/-, and WT female mice were used for mating with males of similar background and genetic modification. Blood pressure was measured, by telemetry, before, during the pregnancy and until 3 days after delivery. The endothelial function was examined using isolated vessel preparations. The pups and placenta weight were assessed, as well as placental gene expression for RAS components and protein expression for VEGF- receptor. We also analyzed the hemodynamic of umbilical artery, on 19th pregnancy day, by ultrasound, as well as a renal function and a cytokine circulating levels. RESULTS: The female mice FVB/N MAS KO presented an increased, time-dependent, in the blood pressure levels, during the pregnancy; tendency to increased umbilical arteries resistivity index, fetal growth restriction, proteinuria, oliguria, increase in cytokines andendothelial dysfunction similar to some of the clinical manifestations found in the development of preeclampsia. Concomitantly with this finding, the deficiency in the MAS KO mice, in the genetic background C57Bl/6, resulted in the normal blood pressure levels, in the beginning, which remained until the end of pregnancy, although without the presence of proteinuria. However, in late pregnancy these females showed a pressure peak, with marked proteinuria, oliguria, increased cytokines, endothelial dysfunction, as well as a fetal growth restriction, demonstrating that the consequences of the MAS deletion, in pregnancy, is background dependent. In addition in the vasodilator axis of theRAS, the ACE2 deletion caused, in females, increased blood pressure before pregnancy. This phenotype was kept throughout the gestational period, associated, also, with striking fractional excretion of protein and fetal growth restriction, featuring some of the clinical symptoms observed in the context of women who develop preeclampsia superimposed onthe chronic arterial hypertension. CONCLUSION: The genetic deletion of the RAS-vasodilatatory axis components leads to abnormal hemodynamic adjustment during pregnancy, mainly characterized by elevated blood pressure in late pregnancy and fetal growth restriction in mice. These data support an important role of the ACE2 / Ang-(1-7) / Mas axis in the fetal development and hemodynamic adjustment during pregnancy, suggesting that this axis may be an important therapeutic target for the treatment of existing changes during pregnancy.