The immune and metabolic phenotype is changed in fetal livers upon systemic sFLT1 expression in preeclamptic mice which is linked to adverse offspring metabolic responses

Preeclampsia (PE) is characterized by increased levels of the soluble fms-like tyrosine kinase-1 (sFLT1), placental dysfunction and fetal growth restriction (FGR). Fetal adaptions to adverse intrauterine environment due to PE can negatively pre-program the fetal/offspring’s metabolism and immune phenotype resulting in long-term metabolic changes. Here we explore the consequences of increased anti-angiogenesis during pregnancy upon PE on the fetal and offspring’s metabolic health in adulthood by using hsFLT1-transgenic mice with systemic human sFLT1 (hsFLT1) overexpression. Histological and molecular analyses of fetal (18.5 dpc) and offspring (P90) livers were performed. Also innate leucocytes populations in fetal livers at 14.5 dpc were investigated by FACS analysis. The immune status of hsFLT1 overexpressing fetuses at 14.5 dpc revealed a sex-independent increased level of leucocytes, mast cells and monocytes compared to controls. At 18.5 dpc, hsFLT1 overexpression resulted in growth-restricted fetuses with reduced liver weight, reduced hepatic glycogen storage and increased hemorrhages and hepatocyte apoptosis. This was associated with altered metabolic gene expression analysing fatty acid/glucose/glycogen metabolism. Males were more affected than females. Postnatal follow-up showed an increased weight gain of male PE offspring resulting in increased body and liver weight at P90, combined with increased serum levels of Insulin and Leptin, both positively correlating with the increased body weight in males. Our results suggest that hsFLT1-related PE/FGR in mice lead to altered fetal liverdevelopment and immune status which could be linked to the adverse metabolic pre-programming of the offspring, affecting males most profoundly.