Oral Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

Replacement of angiotensin-converting enzyme 2 (ACE2) in vitro can reduce oxidative stress in the human FGR placenta (128377)

India A Brooker 1 2 , Jessie M Sutherland 1 2 , Eugenie R Lumbers 1 2 , Joshua J Fisher 3 4 , Kirsty G Pringle 1 2
  1. School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia
  2. Women's Health Research Program, Hunter Medical Research Insitute, New Lambton Heights, New South Wales, Australia
  3. Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
  4. School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia

Fetal growth restriction (FGR) is a serious pregnancy disorder associated with increased fetal morbidity and mortality. FGR is characterised by placental oxidative stress resulting from impaired placentation and subsequent intermittent hypoxia and reoxygenation (H/R). We previously showed that placental antioxidant angiotensin-converting enzyme 2 (ACE2) mRNA expression is decreased in FGR. This study aimed to characterise placental ACE2 activity in FGR and its relationship to placental oxidative stress. Moreover, using an in vitro H/R model in FGR explants, we sought to determine whether ACE2 replacement could mitigate H/R-induced placental oxidative stress.

Placental villous tissue was collected from control (n=35) and FGR (n=15) pregnancies. Of the FGR tissue, n=4 were dissected into villous explants and cultured for 24hrs under normoxia (8% O2) or H/R conditions (6hr cycles of 1% and 8% O2) and treated with or without recombinant human (rh)ACE2. ACE2 activity and markers of oxidative stress were assessed in both whole tissue and explants.

ACE2 activity was significantly decreased in FGR placentae compared with controls (p=0.006), which was accompanied by increased pro-oxidative xanthine oxidase activity (p=0.004) and reduced antioxidant catalase activity (p=0.011). When determining the effect of H/R on FGR explants, ACE2 activity was significantly decreased following exposure to H/R compared with normoxia (p=0.045). While H/R had no significant effect on xanthine oxidase, H/R significantly reduced catalase activity in FGR explants compared with normoxia (p=0.044). Treatment with rhACE2 during H/R partially reversed these effects by significantly increasing FGR explant ACE2 and catalase activity (p=0.037 and 0.015, respectively) compared with H/R alone.

This study demonstrates that FGR placentae exhibit reduced ACE2 activity and that this is associated with oxidative stress. Moreover, replacing ACE2 in vitro during H/R insult to FGR explants partially reversed the effects of H/R, a finding that offers unique potential for treating pregnancies with FGR.