Therapeutic potential and molecular mechanisms of L-citrulline in preeclampsia and fetal reprogramming

• Applicant: Andy WC Man, Ph.D.
• Subject Area: Pharmacology ; Cardiology, Angiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508418089

Preeclampsia, characterized by hypertension, proteinuria and fetal growth restriction, is one of the leading causes of maternal and perinatal mortality. Preeclampsia can leave long-term metabolic and cardiovascular risk to both mother and offspring. Unfortunately, due to the complex etiology of preeclampsia and safety concerns on drug usage during pregnancy, there is no effective pharmacological therapy for preeclampsia so far. The amino acid L-citrulline is the natural precursor of L‐arginine and nitric oxide (NO), which is important for regulating vascular function. In a recent published study, we have obtained promising results showing that L-citrulline supplementation reduces gestational hypertension and improves placentation and fetal growth in a rat model of superimposed preeclampsia. Although L-citrulline is known to increase NO production, the detailed mechanisms underlying the observed effects remain elusive. In the proposed project, we aim to dissect the NO-dependent and -independent mechanisms of L-citrulline in regulating placentation, and to examine the potential fetal reprogramming effects and epigenetic mechanisms of maternal L-citrulline treatment in reducing the risk of cardiometabolic complications of the offspring in adult age. The long-term objective of the study is to establish preeclampsia therapies (L-citrulline and other drugs developed based on the identified mechanisms) with triple beneficial effects protecting the preeclamptic mother, the developing fetus and the offspring in adult age.

• DFG Programme: Research Grants