Abstract 092: Uterine Artery Dysfunction in ACE2 Deficient Mice is Associated with Placental Hypoxia and Reduced Umbilical Flow
Intrauterine fetal growth restriction (IUGR), one of the serious complications of pregnancy, increases the risk for perinatal morbidity and mortality, and cardiovascular and renal abnormalities later in life. The components of the renin-angiotensin system (RAS) are important mediators of uteroplacental vasculature during pregnancy. The distribution of angiotensin converting enzyme 2 (ACE2), a key enzyme of the RAS, is described in the invading and intravascular trophoblasts, decidual cells and in the umbilical cord. Deletion of ACE2 restricts fetal weight gain and reduces fetal-to-placental weights ratio. ACE2 deficiency results in augmented uterine artery contractility to Ang II at mid-gestation. In this study we determined whether uterine artery dysfunction is associated with placental abnormalities in ACE2 KO mice at mid-gestation. Systolic blood pressures were higher in pregnant ACE2 KO vs. C57BL/6 wild type (WT) (102.3±5.1 vs. 85.1±1.9 mmHg). Urinary protein excretion, serum creatinine, mean kidney or heart weights were not different in ACE2 KO vs. WT. Fetal weight, normalized to tibia length, and pup-to-placental weight ratio were lower in ACE2 KO vs. WT (p<0.05). A higher sensitivity to Ang II (pD2 8.64±0.04 vs. 8.5±0.03, p<0.05) concomitantly with a greater active uterine arterial tension tested as the response to KCl 75 mM (1.90±0.15 vs. 1.13±0.12 mN/mm, p<0.05) were associated with lower Ang II receptor 2 (AT2R) protein expression (0.2±0.01 vs. 0.4±0.01, p<0.05) in uterine arteries from pregnant ACE2 KO. In the placenta, trophoblast invasion as assessed by the distribution of cytokeratin in trophospongium and decidual areas was not different between ACE2 KO and WT mice. The staining for pimonidazole, a marker of placental hypoxia, was significantly increased in the trophospongium and placental labyrinth of the ACE2 KO vs. WT (p<0.05). Umbilical artery velocities measured using VEVO 2100 ultrasound were lower in the ACE2 KO vs. WT mice (82.2±13.1 vs. 162.6±35.4 mm/s, p<0.05). In summary, ACE2 deficiency induces uterine artery dysfunction associated with placental hypoxia and reduced umbilical flow. These changes develop before the major growth of fetus occurs and may contribute to the exacerbation of IUGR in the ACE2 KO mice.
Author Disclosures: L.M. Yamaleyeva: None. V.M. Pulgar: None. S.H. Lindsey: None. J. Varagic: None. C.M. McGee: None. L. Yamane: None. K. Brosnihan: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2014 by American Heart Association, Inc.