Sildenafil therapy normalizes the aberrant metabolomic profile in the comt -/- mouse model of preeclampsia/fetal growth restriction

Abstract

Preeclampsia (PE) and fetal growth restriction (FGR) are serious complications of pregnancy, associated with greatly increased risk of maternal and perinatal morbidity and mortality. These complications are difficult to diagnose and no curative treatments are available. We hypothesized that the metabolomic signature of two models of disease, catechol-O-methyl transferase (COMT -/-) and endothelial nitric oxide synthase (Nos3 -/-) knockout mice, would be significantly different from control C57BL/6J mice. Further, we hypothesised that any differences in COMT -/- mice would be resolved following treatment with Sildenafil, a treatment which rescues fetal growth. Targeted, quantitative comparisons of serum metabolic profiles of pregnant Nos3 -/-, COMT -/- and C57BL/6J mice were made using a kit from BIOCRATES. Significant differences in 4 metabolites were observed between Nos3 -/- and C57BL/6J mice (p < 0.05) and in 18 metabolites between C57BL/6J and COMT -/- mice (p < 0.05). Following treatment with Sildenafil, only 5 of the 18 previously identified differences in metabolites (p < 0.05) remained in COMT -/- mice. Metabolomic profiling of mouse models is possible, producing signatures that are clearly different from control animals. A potential new treatment, Sildenafil, is able to normalize the aberrant metabolomic profile in COMT -/- mice; as this treatment moves into clinical trials, this information may assist in assessing possible mechanisms of action.