Postpartum administration of eplerenone to mitigate vascular dysfunction in mice following a preeclampsia-like pregnancy

Abstract

Preeclampsia is a severe pregnancy complication associated with substantial injury to systemic vasculature, major organs, and the feto-placental unit, with an approximate mortality rate of 76,000 pregnant women and 500,000 babies each year. Preeclampsia results in up to five-fold increased risk of cardiovascular disease. There is currently no cure and limited treatment options for preeclampsia and its long-term effects. In this study, we modelled preeclampsia in the mouse via nitric oxide blockade and examined the effect of therapeutic intervention during pregnancy (esomeprazole) and postpartum (eplerenone) on indices of cardiovascular health. Pregnant CBA x C57BL/6 mice received 50 mg/kg/day N(ω)-nitro-L-arginine methyl ester to induce a preeclampsia-like phenotype. Mice were treated with either 12.5 mg/kg/day esomeprazole during pregnancy, 55.5 mg/kg/day eplerenone during the postpartum period, or both esomeprazole and eplerenone in sequence. Mice were hypertensive during pregnancy, fetal growth was restricted by 10%, and maternal vasoactivity was impaired at 5-weeks postpartum. Eplerenone treatment (± esomeprazole) reduced vasoconstriction at 5-weeks postpartum and enhanced vasorelaxation at 5- and 10-weeks postpartum, supporting improved cardiovascular indices in the medium to long term postpartum period. Postpartum eplerenone treatment may be beneficial in mitigating consequent cardiovascular disease risk following a pregnancy complicated by preeclampsia.

Keywords: Cardiovascular disease; Eplerenone; L-NAME; Mouse model; Preeclampsia; Pregnancy.

Fig. 1

L-NAME induced a preeclampsia-like pregnancy. On gestational day 17.5, mean arterial blood pressure was significantly higher in mice receiving L-NAME (vehicle) compared to normal pregnant mice (normal) (a). The blood pressure of mice receiving L-NAME and treated with esomeprazole (ESO) was not significantly different from vehicle or normal pregnant. Pup weight at birth was significantly lower from mice receiving L-NAME, with or without esomeprazole treatment, compared with pups from normal pregnant mice (b). Data are mean ± SEM, n = 16–31, **p < 0.01, ****p < 0.0001.

Fig. 2

A preeclampsia-like pregnancy in mice did not affect postpartum blood pressure. Measured weekly from the time of littering until 10 weeks postpartum, mean arterial blood pressure did not differ significantly between mice that had a preeclampsia-like pregnancy (vehicle) and those that had a normal pregnancy (normal). Treatment with esomeprazole (ESO) during pregnancy, eplerenone (EPL) during the postpartum period, or both therapeutics sequentially (ESO + EPL) did not affect postpartum blood pressure either. Data are mean ± SEM.

Fig. 3

Sequential esomeprazole and eplerenone treatment decreases vasoconstriction. Excised mesenteric arteries from mice that had a preeclampsia-like pregnancy (vehicle) had increased vasoconstriction to phenylephrine at 5 weeks postpartum compared to mice that had a normal pregnancy (normal) (a). Sequential treatment with esomeprazole during pregnancy and eplerenone during the postpartum period (ESO + EPL) significantly reduced vasoconstriction. Eplerenone alone (EPL) had a moderate reduction in vasoconstriction, while esomeprazole alone (ESO) had no effect. No significant differences were observed at 10 weeks postpartum (b). Constriction response to phenylephrine was normalised to the maximal constriction to high potassium solution (KPSS). Data are mean ± SEM, n = 6–8, *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 4

Postpartum eplerenone treatment increases vasorelaxation. There was no difference in vasorelaxation to acetylcholine in excised mesenteric arteries from mice that had a preeclampsia-like pregnancy (vehicle) compared to mice that had a normal pregnancy (normal) at 5 (a) and 10 (b) weeks postpartum. At both timepoints, eplerenone (EPL) significantly increased vasorelaxation, esomeprazole (ESO) had no effect, and sequential esomeprazole and eplerenone (EOS + EPL) reduced vasorelaxation at one dose of acetylcholine. Data are mean ± SEM, n = 6–8, *p < 0.05, **p < 0.01.

Fig. 5

Serum and urine markers of cardiovascular and renal function did not change. At both 5 and 10 weeks postpartum, serum concentrations of CRP (a,b, respectively) and ET-1 (d,e, respectively) were not significantly different between mice that had a normal pregnancy (normal) and mice that had a preeclampsia-like pregnancy (vehicle). Similarly, treatment with esomeprazole alone (ESO), eplerenone alone (EPL), or sequential esomeprazole and eplerenone (ESO + EPL) did not affect serum CRP or ET-1 concentrations at either time point. Urine albumin to creatinine ratio at both 5 and 10 weeks postpartum was not significantly different between mice that had a normal pregnancy and mice that had a preeclampsia-like pregnancy (c,f, respectively). Similarly, treatment with ESO alone, EPL alone, or sequential ESO + EPL did not affect urine albumin to creatinine ratio. Data are mean ± SEM, n = 7–8.