Role of tetrahydrobiopterin in the pathophysiology and long term complications of preeclampsia: a randomised controlled trial in mothers and offspring (Dr Annabelle Frost)

Preeclampsia complicates 3-8% of pregnancies and is a major cause of maternal and fetal morbidity and mortality.

The pathogenesis is multifactorial but endothelial dysfunction is central to the clinical syndrome and sequelae for both mother and child.

Recently, the groups I propose to work with have implicated reduced tetrahydrobiopterin (BH4) bioavailability as potentially critical to this vascular dysfunction.

Mice with endothelial-specific BH4 depletion, a required co-factor for eNOS stability, develop preeclampsia-like syndromes and their offspring have higher blood pressure.

Increased BH4 availability, through dietary supplementation with 5-methyltetrahydrofolate (5-MTHF), which reduces BH4 oxidation, rescues the phenotype.

Increased BH4 levels also restore vasculogenic capacity of endothelial cells collected in clinical studies of hypertensive pregnancies.

I now propose to investigate whether the BH4/eNOS/5-MTHF pathway represents a rational target for vascular protection during preeclampsia.

I will test how dietary supplementation with 5-MTHF affects circulating biomarkers of the pathway in a clinical study of women with early onset preeclampsia and whether they associate with cellular, physiological and clinical characteristics of the pregnancy.

I will then investigate whether maternal supplementation also influences circulating biomarkers in the offspring and to what extent vasculogenic potential of fetal endothelial cells is restored.