Nitric Oxide Dynamics in Pregnancy and Hypertensive Disorders

During normal gestation, nitric oxide (NO) produced by nitric oxide synthase (NOS) enzymes in the endothelium and placental tissues orchestrates a finely tuned vasodilatory programme that ensures progressive uteroplacental blood flow and supports foetal growth. Endothelial NOS (eNOS) activity rises throughout pregnancy, increasing circulating nitrite and nitrate levels, and contributes to the quiescence of the uterine myometrium. In hypertensive disorders of pregnancy, notably pre-eclampsia, placental malperfusion and oxidative stress impair NOS expression and NO bioavailability, leading to maternal endothelial dysfunction, elevated vascular resistance and impaired foetal perfusion. Endogenous inhibitors such as asymmetric dimethylarginine (ADMA) further blunt eNOS activity. Altered NO dynamics underpin clinical manifestations ranging from hypertension and proteinuria to intrauterine growth restriction. Nutritional and pharmacological strategies targeting the L-arginine–NO axis have therefore emerged as promising interventions to restore vascular balance and improve maternal and neonatal outcomes.

Research from Nature Portfolio

Meta-analysis of randomised controlled trials has demonstrated that prenatal oral L-arginine supplementation significantly reduces the incidence of intrauterine growth restriction and pre-term birth, while increasing birth weight, gestational age and Apgar scores in women at high obstetric risk, supporting moderate to high quality evidence for its clinical benefit.

Emerging work on placental polyamine metabolism has revealed that escape from X chromosome inactivation of the spermine synthase gene leads to sex-dependent elevations in polyamine levels within trophoblasts. Polyamine depletion was shown to reduce glycolytic and oxidative phosphorylation pathways, lower acetyl-coA availability, and provoke global histone hypoacetylation, thereby suppressing progesterone biosynthesis. These findings identify an epigenetic circuit that may intersect with NO signalling to regulate vascular tone and placental adaptation.

Nitric Oxide Dynamics in Pregnancy and Hypertensive Disorders publication trend

The graph below shows the total number of articles in nitric oxide dynamics in pregnancy and hypertensive disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Nitric oxide (NO): A gaseous signalling molecule produced by NOS that mediates vasodilation and vascular homeostasis.

Nitric oxide synthase (NOS): Enzymes (eNOS, nNOS, iNOS) that oxidise L-arginine to generate NO and citrulline.

L-arginine: A semi-essential amino acid and substrate for NOS, central to NO production.

L-citrulline: A precursor to L-arginine that enhances endogenous NO synthesis by recycling pathways.

Asymmetric dimethylarginine (ADMA): An endogenous inhibitor of NOS that competes with L-arginine and reduces NO output.

Pre-eclampsia: A hypertensive disorder of pregnancy characterised by new-onset hypertension and organ dysfunction, linked to impaired NO signalling.

References

1. Nitric oxide synthase activity in human trophoblast, term placenta and pregnant myometrium. Reproductive Biology and Endocrinology (2003).
2. Placental Ischemia Says “NO” to Proper NOS-Mediated Control of Vascular Tone and Blood Pressure in Preeclampsia. International Journal of Molecular Sciences (2021).
3. Effects of prenatal oral l-arginine on birth outcomes: a meta-analysis. Scientific Reports (2021).
4. Placental sex-dependent spermine synthesis regulates trophoblast gene expression through acetyl-coA metabolism and histone acetylation. Communications Biology (2022).
5. L‐Arginine and L‐Citrulline for Prevention and Treatment of Pre‐Eclampsia: A Systematic Review and Meta‐Analysis. BJOG An International Journal of Obstetrics & Gynaecology (2025).
6. CHronic hypERtension and L-citRulline studY (CHERRY): an Early-Phase Randomised Controlled Trial in Pregnancy. Reproductive Sciences (2023).