Preeclampsia is a devastating complication of pregnancy featuring profound injury to systemic vasculature, major organs, and the feto-placental unit, and kills approximately 70,000 pregnant people and 500,000 babies each year. Having a pregnancy complicated by preeclampsia results in serious increased (up to 5-fold) risk of subsequently developing cardiovascular disease. Here we model preeclampsia in the mouse via nitric oxide blockade and examine the effect of therapeutic intervention during pregnancy (esomeprazole; proton pump inhibitor) and postpartum (eplerenone; aldosterone antagonist) with respect to long-term indices of cardiovascular health.
CBA x C57BL/6 female mice consuming increased salt (0.9% NaCl drinking water), received 50mg/kg/day N(ω)-nitro-L-arginine methyl ester from pregnancy day (D)7.5 to block nitric oxide production and induce a preeclampsia-like phenotype. Mice were treated with 12.5mg/kg/day esomeprazole during pregnancy, alone or in combination with 55.5mg/kg/day eplerenone during the postpartum period. Maternal blood pressure was measured via tail cuff plethysmography throughout pregnancy (D13.5, D15.5, D17.5) and weekly postpartum (up to 10 weeks). Fetal growth was assessed at birth, and the mesenteric arcade collected for assessment of vasoactivity (via wire myography) at 5- and 10-weeks postpartum.
This model generates a preeclampsia-like pregnancy with maternal hypertension (elevated blood pressure at D17.5 of gestation) and significant fetal growth restriction. We also observed impaired maternal vasoactivity at 5-weeks postpartum. Esomeprazole treatment during gestation modestly reduced maternal hypertension, but did not rescue fetal growth, nor improve vasoactivity at 5- or 10-weeks postpartum compared to control (vehicle treated). Postpartum eplerenone treatment (± esomeprazole during gestation) resulted in significant improvements in maternal vasoactivity, directly demonstrating reduced vasoconstriction to phenylephrine at 5-weeks postpartum and enhanced vasorelaxation to acetylcholine at 10-weeks postpartum, suggestive of improved postpartum cardiovascular indices.
In our mouse model of preeclampsia with postpartum investigation of cardiovascular health, administration of eplerenone postpartum significantly improves vasoactivity at 5-weeks following a preeclampsia-like pregnancy.