237. Metabolomic analysis of preeclampsia in mouse overproducing sFlt-1

Abstract

Preeclampsia (PE) constitutes a leading cause of maternal morbidity and mortality. Although alterations in circulating angiogenic factors are pathogenic, the detailed pathological mechanisms of PE remain unclear. In this study, we performed mass spectrometry (MS)-metabolomics of the plasma and placenta of mice overproducing sFlt-1 to elucidate the pathological conditions of PE. In addition, we evaluated the effect of nicotinamide on metabolic changes in PE. To generate the PE model, recombinant adenovirus to overproduce sFlt-1 was administered to mice (C57BL/6) at 8.5 dpc. Plasma and placenta samples were harvested at 12.5 dpc for metabolomics and gene expression analysis. Blood pressure of PE mice was significantly increased, and fetal weight was significantly decreased. Metabolomics revealed that levels of acylcarnitines in the plasma and placenta were significantly higher in PE mice than controls. In addition, placental acetylcarnitine were increased in the labyrinth as assessed by MS imaging. In the labyrinth, although the levels of metabolites involved in the TCA cycle did not change, those involved in glycolysis and ATP production were decreased in PE mice. Nicotinamide treatment normalized acylcarnitine levels and ATP content in the placenta. Furthermore, nicotinamide increased the levels of NAD+ and the amount of metabolites in glycolysis and TCA cycle that are produced in the enzymatic reactions requiring NAD+. These results indicate that in the PE placenta ATP production is diminished, and fatty acid oxidation is accelerated, and consequently, blood carnitine and acylcarnitines were increased. Targeting this metabolic alteration in the placenta using nicotinamide may be useful to treat PE.