Work

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

Year: 2025

Type: article

Abstract: 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. Term placental explants were exposed to normoxia (8% O 2 ) 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% O 2 ), 5 hrs normoxia). Oxidative stress markers, and ACE and ACE2 mRNA, protein, or activity were assessed. 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). 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. • Placental angiotensin-converting enzyme 2 (ACE2) is increased with a single hypoxia/reoxygenation event. • ACE2 supplementation mitigates the oxidative enzyme NADPH oxidase 5 with hypoxia/reoxygenation. • ACE2 drives Nrf2 antioxidant signalling in the placenta following hypoxia/reoxygenation.

Source: Placenta

DOI: 10.1016/j.placenta.2025.04.008