Eplerenone lowers maternal blood pressure in a model of leptin-induced preeclampsia, but decreases fetal growth when administered mid-, but not late-, gestation.

Abstract

Preeclampsia induces adverse cardiovascular outcomes for both mother and offspring. We established a novel leptin-induced mouse model of preeclampsia that induces hypertension, endothelial dysfunction, and fetal growth restriction, which are collectively ablated by endothelial cell mineralocorticoid receptor (MR) deletion. However, literature lacks preclinical evidence to use MR antagonism for preeclamptic patients. We hypothesize that eplerenone improves blood pressure, vascular function, and fetal outcomes in leptin-infused pregnant mice. We infused timed-pregnant Balb/c mice with saline (sham) or leptin via subcutaneous osmotic minipump and administered vehicle or eplerenone from gestation day (GD) 11-18 and GD15-18. We measured mean arterial blood pressure (BP) via radiotelemetry, vascular function in second-order mesenteric arteries by wire myography, and pup/placental weights on GD18. Eplerenone from GD11-18 ablated leptin-induced increases in BP but independently decreased fetal weight and placental efficiency. Eplerenone increased vascular contractility to phenylephrine and increased mRNA expression of NADPH oxidase (NOX) 1 and 2 in the placentas of pregnant mice in the GD11-18 cohort. We observed in our GD15-18 cohort that eplerenone no longer decreased fetal weight or placental efficiency and there was no increase in contractility to phenylephrine. In conclusion, our data suggest that although eplerenone improves leptin-induced hypertension in pregnant mice, eplerenone reduces fetal weight when administered at mid-, but not late-, gestation in pregnant mice.There are limited advances in the treatment for preeclampsia. Leptin induces preeclampsia dependent on mineralocorticoid receptor (MR) activation; however, there is little preclinical data on the use of MR antagonists in hypertensive pregnancy. When administered at midgestation in hypertensive mouse pregnancy, eplerenone lowers blood pressure, but increases vasoconstriction in mesenteric arteries and reduces fetal growth. When administered later in pregnancy, eplerenone no longer restricts fetal growth or increases vasoconstriction.