Pregnancy Shifts ACE2/ACE Balance to Ang-(1-7)

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Our group first showed that angiotensin-(1-7) [Ang-(1-7)] increases in the plasma and urine of normal pregnant women. In preeclamptic pregnant subjects we demonstrated a decrease of plasma Ang-(1-7) greater than that of Ang II. These initial findings provide a basis for an important physiological role for Ang-(1-7) in the course of pregnancy and in pregnancy-induced hypertension (PIH) where there may be a diminished influence of Ang-(1-7) to oppose the local tissue actions of Ang II. New data from our laboratory showed that Ang-(1-7) enhanced mesentery artery dilation in pregnancy and this was accompanied by increased kidney and urine levels of Ang-(1-7) in normal pregnant rats. Preliminary studies showed that urinary excretion of Ang-(1-7) was reduced in an animal model that resembles PIH. In addition, our recent discovery that angiotensin converting enzyme 2 (ACE2), a carboxypeptidase that exhibits high efficacy for Ang II metabolism to Ang-(1-7), is present in the kidney and uterus of pregnant rats, is localized to similar regions in kidney and uterus as Ang-(1-7), and is up-regulated in pregnancy suggests the hypothesis that increased expression of ACE2 leads to an enhanced formation of Ang-(1-7) during pregnancy. The hypothesis to be assessed in these studies is twofold: 1) that pregnancy is a model of overexpression of Ang-(1-7) resulting from increased expression of ACE2; 2) that the resulting hemodynamic profile (i.e the decreased peripheral resistance seen in normal pregnancy) is dependent upon up-regulation of ACE2 leading to enhanced formation of Ang-(1-7), whereas PIH (characterized by increased total peripheral resistance and uteroplacental ischemia) is due to unbridled pressor/ischemic actions of Ang-II as a consequence of a marked reduction of the formation and vasodepressor effects of Ang-(1-7). The Specific Aims are: 1) to assess the evolutionary expression of Ang-(1-7) and ACE2 at early, mid and late gestation in normal and the reduced uterine perfusion pressure (RUPP) pregnant rats; 2) to determine the contribution of the ACE2 pathway to Ang-(1-7) formation at early, mid and late gestation in normal pregnant and RUPP pregnant rats; 3) to assess the systemic and regional hemodynamic role of Ang-(1-7) and ACE2 in normal and RUPP pregnant rats; and 4) to characterize the null ACE2-/- pregnant mouse by detertm'ning the impact of the loss of the gene on blood pressure regulation. The proposed research will establish a novel and significant new dimension to the contribution of the RAS in the physiology and pathology of pregnancy.