Epidemiological data shows that an adverse intrauterine environment increases the susceptibility for cardiovascular and metabolic diseases later in life. However, conclusive data on causative factors and molecular mechanisms is lacking. Here we compare maternal and fetal phenotypic and molecular consequences of preeclampsia at the end of gestation. To that end, we employed three C57Bl/6J mouse models mimicking specific parts of the phenotype of preeclampsia: the sFlt+LPS model, a combination of an antiangiogenic and a proinflammatory factor, the L-NAME model, where vasoconstriction is induced, and the LXR agonist model, which has been shown to induce metabolic distortion and antiangiogenesis. The direct consequences of these models were examined at gestational day 18.
Elevated maternal systolic blood pressure was found in sFlt+LPS and L-NAME dams. Maternal circulating insulin, an important fetal growth factor, was found decreased in the LXR model, while no changes were found in free thiols, a measure of oxidative status. Direct consequences for fetuses were model- and sex-specific. LXR and sFlt+LPS fetuses were growth restricted, with brain sparing taking place in male fetuses only. Placental efficacy, as measured by BW/placenta ratio, was lower for male LXR and L-NAME fetuses. In the sFlt1+LPS-model, sex-specific alterations in levels of several metabolic genes that could be involved in fetal programming were found, including Srebf2. Furthermore, Srebf2 DNA methylation was found decreased in those samples.
With the sFlt1+LPS model being the most comprehensive preeclampsia model, a long-term experiment to follow offspring’s health has been performed. As expected, blood pressure, body weight gain and body composition of the sFlt1+LPS-exposed offspring was altered, which was accompanied by molecular changes. To conclude, we show here that differences in maternal circulating factors have distinct direct effects on fetal growth and gene expression, which can modulate long-term cardiometabolic health of the offspring.