Oral Presentation ESA-SRB 2023 in conjunction with ENSA

The role of ACE2 in protecting against placental oxidative stress induced by hypoxia/reoxygenation (#121)

India Brooker 1 2 , Sarah Delforce 1 2 , Joshua Fisher 2 3 , Jessie Sutherland 1 2 , Saije Endacott 1 2 , Eugenie Lumbers 1 2 , Kirsty Pringle 1 2
  1. School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia
  2. Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
  3. School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia

Fetal growth restriction (FGR) is a leading cause of infant morbidity and mortality characterised by deficient placentation. Consequently, the placenta experiences intermittent hypoxia and reoxygenation (H/R), which induces a state of oxidative stress. FGR placentae also have reduced antioxidant capacity, including reductions in the critical antioxidant enzyme of the renin-angiotensin system, angiotensin-converting enzyme 2 (ACE2). This study aimed to model placental H/R in vitro and investigate the role ACE2 plays in the placental pathophysiology of FGR.

Healthy term human placental villous explants (n=7) were cultured in normoxic (8% O2, 6hrs) or acute H/R (1hr in 1% O2, 5hrs in 8% O2) conditions. During culture, explants were treated with diminazene aceturate (DIZE) or recombinant human (rh)ACE2 to activate or replace placental ACE2, respectively. Subsequently, ACE2 expression, oxidative stress markers (nicotinamide adenine dinucleotide phosphate oxidase (NOX4 and NOX5)), and antioxidant capacity (catalase and superoxide dismutase) were assessed.

Exposure to acute H/R increased placental ACE2 mRNA expression (P=0.041), an unexpected outcome as physiologically, FGR placentae exhibit a decrease in ACE2. Despite enhanced antioxidant potential with elevated ACE2, the mRNA expression of oxidative stress markers NOX4 and 5 were significantly increased by H/R (P=0.013 and 0.008, respectively), with NOX5 significantly correlated to ACE2 (P=0.049, r=0.756). Moreover, placental superoxide dismutase activity was decreased (P=0.002), while catalase activity was increased (P=0.03) with acute H/R. Treatment with DIZE or rhACE2 were unable to ameliorate the acute H/R-induced upregulation of NOX4/5 expression or alter superoxide dismutase and catalase activity compared to vehicle controls.

We have for the first time shown that under acute H/R conditions, placental ACE2 expression is upregulated but is unable to overcome oxidative stress induced by enhanced NOX4 and 5 expression. Further research exploring the effects of prolonged H/R, which is likely to exhaust ACE2 and more closely reflect the FGR placenta, are warranted.