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

ACE2缺乏症：母体和胎儿生长受限的新模式。

• 批准号: 8385415
• 负责人: Kathleen Bridget Brosnihan
• 金额: $ 22.2万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385415
• 关键词: Address; Affect; Angiotensins; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Blood; Blood Plasma Volume; Blood Pressure; Blood flow; Cardiovascular Physiology; Cardiovascular system; Cell Mobility; Cells; Chymosin; Cleaved cell; Complex; Data; Decidual Cell Reactions; Elderly; Embryo; Embryo Transfer; Environment; Enzymes; Equilibrium; Event; Female; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Weight; Genes; Growth; Hemochorial Placental Development; Homeostasis; Homologous Gene; Human; Impairment; In Vitro; Infant; Investigation; Ischemia; Kidney; Knock-out; Knockout Mice; Mediator of activation protein; Metabolic; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Nutrient; Perfusion; Perinatal; Placenta; Placentation; Plasma; Play; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnant Women; Psyche structure; Regulation; Renin-Angiotensin System; Role; Sheep; Spiral Artery of the Endometrium; System; Tissues; Transplantation; Urine; Uterus; Vascular resistance; Weight; Weight Gain; Wit; Women' s Health; angiogenesis; fetal; fetal programming; hemodynamics; high risk; implantation; in utero; in vivo; pregnant; response; tool; trophoblast; uptake; zygote

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. PUBLIC HEALTH RELEVANCE: A new animal model of fetal and maternal growth restriction due to a single genetic alteration opens a new field of investigation for studying the role of the deletion of the ACE2 gene that has been associated with shifts in the balance of Ang II/Ang-(1-7) in maternal and intrauterine growth restriction as well as their interface in the uteroplacental unit.

描述（由申请人提供）：妊娠并发症是妇女健康的主要问题之一。 母体体重是决定胎儿最佳发育的重要因素。 宫内生长受限（FGR）是一种常见且严重的妊娠并发症，与母体体重减轻和/或子宫胎盘灌注不足有关。 暴露于FGR的婴儿在以后的生活中面临许多围产期发病率以及身体和/或精神障碍的高风险。 很少有人知道的 导致子宫胎盘单位功能障碍的分子机制，这是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）的失调可能导致胎盘缺血，这被认为是FGR的原因。 高子宫胎盘血管阻力被认为与FGR有关。 最近，RAS被证明是更复杂的ACE同源物，ACE 2的发现。 该酶将Ang I切割成Ang-（1-9），Ang-（1-9）可被ACE转化成Ang-（1-7）。 它还将Ang II降解为Ang-（1-7）。 ACE 2通过改变Ang II和Ang-（1-7）之间的平衡，以反调节方式对ACE起作用。 我们以前的研究表明ACE 2在正常妊娠的胎盘和母体间质组织中的存在，提示其在已建立妊娠的胎盘形成中的作用。 正常妊娠晚期孕妇血浆和尿液中Ang-（1-7）水平升高。 然而，没有关于妊娠或胎儿生长受限中ACE 2功能的数据。 我们的初步数据表明，在ACE 2（敲除）KO妊娠小鼠中，母体和胎儿生长受限，这与循环Ang-（1-7）减弱和胎盘Ang II增加有关。 假设：ACE 2在胎儿生长和妊娠中起关键作用。 我们将确定ACE 2的缺失是否与平衡的变化有关， Ang Ⅱ/Ang-（1-7）的表达与子宫胎盘血流的改变和FGR有关。 作为拟定研究的结果，由于单一遗传改变，将表征胎儿和母体生长受限的新动物模型。 具体目标1将解决为什么ACE 2缺乏会影响母体体重增加。我们将确定妊娠期间ACE 2丢失的代谢和血流动力学（血浆容量、子宫胎盘流量和血管阻力）后果。 具体目标2将解决子宫胎盘的变化，以应对ACE 2缺乏。 我们将确定ACE 2缺乏是否会在早期改变（着床，蜕膜化，和血管生成）或晚期（滋养层侵入和螺旋动脉重塑的程度）妊娠事件，以及在妊娠早期或晚期将Ang-（1-7）直接施用到子宫胎盘单位中是否会通过将RAS内的平衡向Ang-（1- 7）转移而影响妊娠期间的胎儿生长。 此外，将建立子宫胎盘组织中促/抗炎和促/抗血管生成介质的平衡。 具体目标3将确定母体或胎儿ACE 2 KO是否是使用胚胎移植限制胎儿体重所必需的。 公共卫生关系：由于单一遗传改变而导致的胎儿和母体生长受限的新动物模型为研究基因组的作用开辟了新的研究领域。 ACE 2基因的缺失与母体和胎儿宫内生长受限中Ang II/Ang-（1-7）平衡的变化以及它们在胎儿生长受限中的界面有关。 子宫胎盘单位