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.
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.