A double hit preeclampsia model results in sex-specific growth restriction patterns

Preeclampsia is a multifactorial pregnancy-associated disorder characterized by angiogenic dysbalance and systemic inflammation, however, animal models which combine these two pathophysiological conditions are missing. Here we introduce a novel double-hit preeclampsia mouse model which mimics the complex multifactorial conditions that are present during preeclampsia, and allows for the investigation of early consequences for the fetus. Adenoviral overexpression of soluble fms-like tyrosine kinase (sFlt-1) and lipopolysaccharide (LPS) administration at mid-gestation in pregnant mice resulted in hypertension and albuminuria comparable to that of the manifestation in humans. A metabolomics analysis revealed that preeclamptic dams have increased plasma concentrations of phosphadytilcholines. The fetuses of both sexes were growth restricted, however in males a brain-sparing effect was seen as compensation to this growth restriction. According to the plasma metabolomics, male fetuses showed changes in amino acid metabolism, while female fetuses showed pronounced alterations in lipid metabolism. Our results show that combined exposure to sFlt-1 and LPS mimics the clinical symptoms of preeclampsia and affects fetal growth in a sex-specific manner with accompanying metabolome changes.