ACE2 Deficiency: A new model of maternal and fetal growth restriction.

描述(申请人提供)：妊娠并发症是妇女健康的主要问题之一。孕妇体重是胎儿最佳发育的重要决定因素。宫内生长受限(FGR)是一种常见且严重的妊娠并发症，与孕妇体重减轻和/或子宫胎盘灌注量不佳有关。暴露于FGR的婴儿在晚年患上许多围产期疾病以及身体和/或精神障碍的风险很高。人们对此知之甚少 导致子宫胎盘单位功能障碍的分子机制，是FGR最常见的可识别原因。全身或局部子宫胎盘肾素-血管紧张素系统(RAS)的调节失调可能与胎盘缺血有关，后者被认为是FGR的原因。子宫胎盘血管阻力高被认为与FGR有关。最近，随着ACE同源物ACE2的发现，RAS被证明是更复杂的。该酶将Ang I裂解成Ang-(1-9)，后者可被ACE转化为Ang-(1-7)。它还将Ang II降解为Ang-(1-7)。ACE2通过改变血管紧张素转换酶II和血管紧张素转换酶-(1-7)之间的平衡，对血管紧张素转换酶起反调节作用。我们以前的研究表明，在正常妊娠的人胎盘和母体间质组织中存在ACE2，这表明它在既定妊娠的胎盘形成中发挥了作用。正常妊娠晚期血浆和尿液中Ang-(1-7)水平升高。然而，目前还没有关于ACE2在妊娠或胎儿生长受限中的作用的数据。我们的初步数据表明，在ACE2(基因敲除)KO孕鼠中，母体和胎儿的生长受到限制，这与循环中Ang-(1-7)的减少和胎盘Ang II的增加有关。假设：ACE2在胎儿生长和妊娠中起关键作用。我们将确定是否删除与余额变化相关的ACE2 Ang II/Ang-(1-7)参与子宫胎盘血流改变和FGR。作为拟议研究的结果，一种新的胎儿和母体生长受限的动物模型将因单一的基因改变而被表征。具体目标1将阐述为什么ACE2缺乏会影响母亲的体重增加。我们将确定妊娠期间ACE2丢失对代谢和血流动力学(血浆容量、子宫胎盘血流和血管阻力)的影响。具体目标2将解决因ACE2缺乏而引起的子宫胎盘改变。我们将确定ACE2缺乏是否会改变妊娠早期(着床、蜕膜和血管生成)或晚期(滋养层侵袭和螺旋动脉重塑程度)事件，以及在妊娠早期或晚期直接向子宫胎盘单位注射Ang-(1-7)是否会通过使RAS内的平衡向Ang-(1-7)倾斜而影响妊娠期间的胎儿生长。此外，子宫胎盘组织中的促/抗炎和促/抗血管生成介质的平衡也将被建立。具体目标3将确定使用胚胎移植进行胎儿体重限制是否需要孕妇或胎儿ACE2 KO。

DESCRIPTION (provided by applicant): Pregnancy complications are one of the leading problems in women's health. Maternal weight is an important determinant of optimal fetal development. Intrauterine growth restriction (FGR) is a frequently occurring and serious complication of pregnancy, associated with reduced maternal weight and/or suboptimal uteroplacental perfusion. Infants exposed to FGR are at high risk for numerous perinatal morbidities as well as physical and/or mental impairments in later life. Little is known about the molecular mechanisms leading to a dysfunctional uteroplacental unit, a most common identifiable cause of FGR. Dysregulation within systemic or local uteroplacental rennin-angiotensin system (RAS) may contribute to placental ischemia that is considered to be the cause of FGR. High uteroplacental vascular resistance is thought to be associated wit FGR. Recently, the RAS was shown to be more complex with the discovery of an ACE homologue, ACE2. This enzyme cleaves Ang I into Ang-(1-9) which can be converted to Ang-(1-7) by ACE. It also degrades Ang II to Ang-(1-7). ACE2 acts in a counter-regulatory manner to ACE by shifting the balance between Ang II and Ang- (1-7). Our previous studies showed the presence of ACE2 in human placenta and maternal stromal tissue in normal pregnancy suggesting its role in placentation in established pregnancy. We also showed the increased levels of Ang-(1-7) in plasma and urine of normal pregnant women in the 3rd trimester. However, there is no data on ACE2 function in pregnancy or fetal growth restriction. Our preliminary data demonstrate restricted maternal and fetal growth in the ACE2 (knockout) KO pregnant mouse which was associated with attenuated circulating Ang-(1-7) and increased placental Ang II. Hypothesis: ACE2 plays a critical role in fetal growth and pregnancy. We will establish whether deletion of ACE2 that has been associated with shifts in the balance of Ang II/Ang-(1-7) contributes to alterations in uteroplacental blood flow and to FGR. As a result of the proposed studies, a new animal model of fetal and maternal growth restriction will be characterized due to a single genetic alteration. Specific Aim 1 will address why ACE2 deficiency affects maternal weight gain. We will determine the metabolic and hemodynamic (plasma volume, uteroplacental flow and vascular resistance) consequences of loss of ACE2 during pregnancy. Specific Aim 2 will address uteroplacental alterations in response to ACE2 deficiency. We will determine whether ACE2 deficiency alters early (implantation, decidualization, and angiogenesis) or late (trophoblast invasion and degree of remodeling of spiral arteries) events of pregnancy and whether the direct administration of Ang-(1-7) into the uteroplacental unit at early or late gestation will influence fetal growth during pregnancy by shifting the balance within RAS towards Ang-(1- 7). Moreover, the balance of pro-/anti-inflammatory and pro-/anti-angiogenic mediators in the utero-placental tissues will be established. Specific Aim 3 will determine whether maternal or fetal ACE2 KO is necessary for the fetal weight restriction using embryo transfer.