Mid-late Gestation Eplerenone Treatment Improves Maternal Cardiovascular, But Not Fetal, Outcomes in a Mouse Model of Leptin-induced Preeclampsia

Preeclampsia (PE) induces adverse cardiovascular outcomes for both mother and offspring. We established a novel leptin-induced mouse model of PE 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 PE patients. We hypothesize eplerenone will improve blood pressure, vascular function and fetal outcomes in leptin-infused pregnant mice. We infused timed-pregnant Balb/c mice with saline (sham) or leptin (LEP, 0.9mg/kg/day) via s.c. osmotic minipump and administered vehicle (VEH) or eplerenone (EPL, 200mg/kg/day) from gestation day (GD)11-18 (n=9-15). We measured mean arterial blood pressure (BP) via radiotelemetry, vascular function in 2 nd order mesenteric arteries by wire myography, and pup/placental weights on GD18. We measured uterine artery resistance index (UARI) via ultrasound measurement of peak systolic and end diastolic velocities. Pairwise comparisons were by student’s t-test and myography analyzed by 2-Way ANOVA w/RM, mean±SEM (*p<0.05, **p<0.01). EPL ablated LEP-induced increases in BP (98±4 LEP-EPL vs 113±3LEP-VEH mmHg,*) and prevented LEP from decreasing vascular relaxation responses to acetylcholine, a measure of endothelial function (concentration-response curve, p>0.05 vs SHAM-VEH). LEP decreased placental efficiency and pup weight, however, so also did EPL treatment as an independent variable (pup/placenta ratio: 8.1±0.1 SHAM-VEH, 7.4±0.1 LEP-VEH, 8.1±0.2 SHAM-EPL, 6.9±0.1 LEP-EPL, *for both effect of LEP and EPL), (pup weight: 0.73±0.007g SHAM-VEH, 0.71±0.010 LEP-VEH, 0.71±0.009 SHAM-EPL, 0.66±0.007 LEP-EPL, *for both effect of LEP and EPL). LEP increases plasma endothelin-1 measured via ELISA (2.132±0.389 LEP-VEH vs. 1.359±0.109 SHAM-VEH) and UARI data indicates that EPL treatment increases UARI in leptin-infused pregnant mice (0.52 LEP-VEH vs 0.60 LEP-EPL PSV/EDV). Interestingly, mRNA expression of NADPH oxidase (NOX) 1 and 2 in mouse placenta were significantly increased in the EPL treated mice compared to VEH (∆∆Ct to 18s: 1.2±0.28 SHAM-VEH, 1.1±0.317 LEP-VEH, 1.9±0.3462 SHAM-EPL, 2.9±0.706 LEP-EPL, **, NOX1; 1.1±0.306 SHAM-VEH, 1.1±0.253 LEP-VEH, 1.7±0.369 SHAM-EPL, 3.0±0.684 LEP-EPL, **, NOX2; both for effect of EPL). Collectively, these data suggest that EPL may ablate LEP-induced hypertension and endothelial dysfunction in PE mice. However, EPL did not improve fetal growth in LEP-induced PE. EPL increases NOX1/2, indicating an increase for ROS and may fail to improve placental function induced by leptin, potentiating an increase in UARI and potentially lower fetal blood flow. AHA 24PRE1192508, NIH 1R01HL169576 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.