Characterising the role of placental angiotensin-converting enzyme 2 (ACE2) during the onset of oxidative insult by hypoxia/reoxygenation: Implications for fetal growth restriction.

INTRODUCTION

Fetal growth restriction (FGR) is a leading cause of infant morbidity and mortality. Approximately 60% of FGR cases result from placental dysfunction, often due to defective remodelling of the uterine vasculature and subsequent exposure to hypoxia/reoxygenation that induces oxidative stress. Angiotensin-converting enzyme 2 (ACE2) counteracts the ACE-driven axis of the renin-angiotensin system and is reduced in FGR placentae. We aimed to investigate the role of ACE2 in protecting against placental oxidative stress induced via a hypoxia/reoxygenation event.

METHODS

Term placental explants were exposed to normoxia (8% O2) for 6 hrs or were treated with media alone or recombinant human (rh)ACE2 and exposed to a hypoxia/reoxygenation insult (1 hr hypoxia (1% O2), 5 hrs normoxia). Oxidative stress markers, and ACE and ACE2 mRNA, protein, or activity were assessed.

RESULTS

ACE2 mRNA expression was increased with hypoxia/reoxygenation compared with normoxia (p=0.045). Hypoxia/reoxygenation significantly increased placental mRNA expression of the oxidative enzymes NOX4 and NOX5 compared with normoxia (p=0.021 and 0.023). NOX5 protein was not significantly different between normoxic controls and hypoxia/reoxygenation; however, rhACE2 significantly reduced NOX5 protein levels (p=0.015). Antioxidant activity of SOD decreased (p=0.028), while CAT increased with hypoxia/reoxygenation (p=0.010). Placental Nrf2 and NQO1 mRNA expression increased with rhACE2 compared with hypoxia/reoxygenation alone (p=0.038 and 0.013).

CONCLUSION

We have characterised the redox-sensitive changes that occur in the placenta due to defective placentation and hypoxia/reoxygenation and have shown for the first time the role of placental ACE2 in mitigating oxidative insult associated with hypoxia/reoxygenation.