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

摘要

Introduction: Preeclampsia is a multifactorial pregnancy disorder presented with angiogenic imbalance and low-grade systemic inflammation. Next to detrimental consequences for the mother, preeclampsia has severe long-term effects for the offspring. However, animal models which represent these two pathophysiological conditions are missing. Here we introduce a novel double hit animal model which mimic the complex multifactorial conditions present during preeclampsia. Methods: C57Bl/6 mice were injected with adenovirus over-expressing sFlt-1 or empty adenovirus (first hit: angiogenic imbalance) on gestational day GD 8. On GD 10 a second hit (inflammation) was introduced with a low dose of lipopoly-saccharide (LPS, 25 ug/kg, i.p.) or PBS (control). Between GD 16 and 17, 24 hrs urine was collected. Blood pressure and blood analysis were performed on GD 18. Fetuses and placentas were collected at GD18. Results: Animals exposed to sFlt-1 and LPS showed increased blood pressure and increased proteins and albumin in 24 hrs urine, the clinical hallmark of preeclampsia. sFlt-1 concentrations were 2x higher in the double hit preeclampsia group. Blood pressure values were positively correlated with the sFlt-1 concentrations. Fetuses were growth restricted: females have symmetrical growth restriction accompanied by smaller placentas. In continuation, male fetuses showed asymmetrical growth restriction, accompanied with brain sparing. Conclusion: Our results show that combined exposure to sFlt-1 and LPS mimics the symptoms of preeclampsia in a mouse model and affects the fetal growth in a sex-specific manner.