Abstract 317: ACE2 Deficiency Enhances Angiotensin II-Induced Vasoconstriction Of The Uterine Artery at Mid-Gestation In Mice.
Fetal growth restriction (FGR) remains a leading cause of perinatal morbidity and mortality in humans. Angiotensin converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system that influences the balance between angiotensin II (Ang II) and angiotensin-(1-7) (Ang-(1-7)). ACE2 is highly expressed in the human placenta and maternal stromal tissue in normal pregnancy; however its role in pregnancy is not well understood. Our previous studies revealed that pregnancy in ACE2-deficient mice (ACE2KO) is associated with restricted maternal and fetal weight, attenuated circulating Ang-(1-7), and increased placental Ang II at the end of pregnancy. Since the loss of ACE2 may lead to vascular dysfunction and FGR, we compared the uterine artery reactivity in ACE2KO versus wild-type C57Bl/6 (WT) pregnant mice using wire myography. Maternal and fetal weights and pup-to-placenta ratio were not altered in ACE2KO at day 14 of gestation. However, the number of pups was reduced in ACE2KO [ACE2KO: 7.2±0.2 vs. WT: 9.8±0.7 pups, n=4-5; *p<0.05]. Uterine artery diameters were similar between the two mouse strains. Maximal vasoconstriction to 10 μM phenylephrine (PE) or 80 mM potassium chloride (KCl) and maximal endothelium-dependent relaxation (1 μM acetylcholine) were not altered in pregnant ACE2KO versus pregnant WT. Pregnancy tended to reduce the uterine artery sensitivity to Ang II in WT [virgin: LogEC50: -9.0 vs. 14d pregnant: -8.0, p=0.09], but not in ACE2KO [virgin: LogEC50: -9.1 vs. 14d pregnant: -8.6, p=0.46]. Moreover, the concentration-dependent vasoconstriction to Ang II (0.1 nM-1 μM) was greater in the uterine arteries from pregnant ACE2KO as compared to pregnant WT [ACE2KO: LogEC50: -8.6 vs. WT: -8.0, n=4-5; *p<0.05]. Pretreatment with 1μM Ang-(1-7) for 5 minutes partially attenuated the Ang II-induced vasoconstriction and tended to reduce the sensitivity to Ang II in pregnant ACE2KO [n=2-4]. These results show that the loss of ACE2 in pregnancy is associated with increased constriction and sensitivity of the uterine artery to Ang II. Absence of enhanced constriction to PE or KCl in ACE2KO suggests the specificity of the Ang II-induced response. In conclusion, ACE2 deficiency may contribute to FGR via Ang II-mediated uterine artery dysfunction.
- © 2012 by American Heart Association, Inc.