Abstract 050: Endothelial Cell Mineralocorticoid Receptor Deletion Improves Endothelial Function, Blood Pressure And Fetal Growth In The RUPP Mouse Model Of Preeclampsia

Abstract

Preeclampsia (PE) is a hypertensive disorder of pregnancy that causes adverse pregnancy outcomes. Progesterone in pregnancy increases endothelial mineralocorticoid receptor (ECMR) expression, which we showed mediates endothelial function in hypertensive female mice, however, whether ablating endothelial dysfunction in PE improves pregnancy outcomes is unknown. We hypothesized that improving endothelial function via ECMR deletion increases fetal growth and ablates hypertension in the reduced uterine perfusion pressure (RUPP) PE mouse. Pregnant ECMR-intact (WT) and -deficient (KO) mice underwent RUPP or sham surgery on GD13 and sacrificed on GD18 (WT Sham=9, WT RUPP=5, KO Sham=6, KO RUPP=6). Vascular function was measured via wire myography on 2 nd order mesenteric arteries and thoracic aorta. Systolic blood pressure (BP) was measured by radiotelemetry in a subset of mice. RUPP did not decrease maternal weights in either WT or KO mice (P>0.05) but decreased pup weight (726±20 WT+Sham vs 660±11mg WT+RUPP, *P<0.05) and fetal demise (16±4 vs 28±4% resoprtions/litter, *P<0.05) in WT pregnant mice, however, not in KO mice (710±15 KO+Sham vs 693±19 mg KO+RUPP, P>0.05, and 13±5 vs 28±12% resoprtions/litter, P>0.05), indicating KO protected fetal growth. RUPP reduced endothelial-dependent, acetylcholine-mediated vascular relaxation (10 -9 -3x10 -5 M) in WT, but not KO pregnant mice (*P<0.05, 2-way ANOVA w/ RM), but not aorta ACh-mediated relaxation (P>0.05). Nitric oxide synthase (NOS) inhibitor LNAME ablated differences in ACh-mediated relaxation between WT Sham and WT RUPP (P>0.05), with no differences observed in KO Sham or KO RUPP, in both aorta and mesenteric arteries, indicating RUPP impaired endothelial function via decreasing NOS activity. Preliminary data demonstrates RUPP increased BP on GD15-17 in WT (127±21 mmHg, N=3), however, not in KO pregnant mice (111±4, N=2). RUPP also ablated circadian rhythm in WT, but not KO, pregnant mice from GD15-18. Collectively, these data indicate that ECMR activation induces reduced pup weight, endothelial dysfunction and hypertension in the RUPP model which may lead to clinical studies for consideration of specific MR antagonists as therapeutic options for endothelial dysfunction in PE pregnancies.