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

本课题组首次发现正常孕妇血浆和尿液中血管紧张素-(1-7)[Ang-(1-7)]升高。在先兆子痫孕妇中，血浆Ang-(1-7)的下降幅度大于Ang II。这些初步发现为Ang-(1-7)在妊娠和妊娠高血压综合征(PIH)中的重要生理作用提供了依据。在妊高征中，Ang-(1-7)的影响可能减弱，以对抗Ang II的局部组织作用。我们实验室的新数据表明，Ang-(1-7)增强了妊娠期肠系膜动脉的扩张，并伴有肾脏和尿液的增加。 正常妊娠大鼠血浆Ang-(1-7)水平。初步研究表明，在类似于妊高征的动物模型中，尿Ang-(1-7)的排泄量减少。此外，我们最近发现，血管紧张素转换酶2(ACE2)是一种对Ang-(1-7)具有高效代谢作用的羧肽酶，存在于妊娠大鼠的肾脏和子宫中，定位于与Ang-(1-7)相似的区域，并在妊娠期间上调，这表明ACE2的表达增加导致妊娠期间Ang-(1-7)的形成增强。这些研究中需要评估的假设有两个：1)妊娠是由于ACE2表达增加而导致Ang-(1-7)过度表达的模型；2)由此导致的血流动力学特征(即正常妊娠中外周阻力降低)依赖于ACE2上调导致Ang-(1-7)的形成，而妊高征(特征是总外周阻力增加和子宫胎盘缺血)是由于Ang-(1-7)的形成和血管抑制作用显著减少而导致Ang-II的无节制升压/缺血作用。其具体目的是：1)评估Ang-(1-7)和ACE2在正常妊娠早、中、晚期和降低子宫灌流压(RUPP)大鼠中的进化表达：2)确定ACE2通路在早期Ang-(1-7)形成中的作用， 研究血管紧张素转换酶1-7(Ang-(1-7))和血管紧张素转换酶2(ACE2)在正常妊娠和Rupp妊娠大鼠中、晚期的血流动力学作用，以及ACE2基因缺失对血压调节的影响，以确定ACE2基因缺失对血压调节的影响。这项拟议的研究将为RAS在妊娠生理学和病理学中的贡献建立一个新的和重要的新维度。

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.