Abstract MP14: Endothelial Mineralocorticoid Receptor Deletion Abrogates Leptin-induced Endothelial Dysfunction And Fetal Growth Restriction In Pregnant Mice

Obesity increases preeclampsia (PE) risk. Plasma leptin levels increase with body weight in women with PE, and in addition, placental ischemia, an initiating event of PE, also increases plasma leptin. Our lab has shown that hyperleptinemia induces endothelial dysfunction and hypertension in female mice via endothelial mineralocorticoid receptor (ECMR) activation and that high progesterone levels of pregnancy increases ECMR expression. We hypothesized that leptin infusion induces PE-like endothelial dysfunction in pregnant mice, which is abrogated by ECMR deletion. Pregnant mice were infused with leptin by miniosmotic pump (0.9mg/kg/day, s.c.) on gestation day (GD) 11-18. Leptin decreased pup wt (0.86±0.04g ECMR +/+ vs 0.52±0.11 ECMR +/+ +leptin, *P+/+ vs 42±32 ECMR +/+ +leptin, P=0.09). ECMR deletion rescued pup weight (0.91±0.06g ECMR -/- vs 1.0±0.07 ECMR -/- +leptin) and protected fetal resorptions (2±2% ECMR -/- vs 0±0 ECMR -/- +leptin) in leptin-infused pregnant mice. In association, placental efficiency (pup/placenta ratio) decreased with leptin in ECMR +/+ (9.7±0.7 ECMR +/+ vs 7.9±0.6 ECMR +/+ +leptin, *P-/- (9.6±0.5 ECMR -/- vs 9.4±1.2 ECMR -/- +leptin) mice. Leptin infusion reduced endothelial function (acetylcholine-mediated relaxation) in aortas of ECMR +/+ , but not ECMR -/- , pregnant mice (2-way ANOVA, repeated measures, *P-/- +leptin mice was due to preserved NO bioavailability. No changes in endothelial-independent sodium nitroprusside or contractile responses to phenylephrine, serotonin or KCl were observed. ECMR deletion reduced aorta IL-1β mRNA (0.5±0.1-fold change ECMR +/+ +leptin vs 0.2±0.1-fold change ECMR -/- +leptin, P=0.06) levels and also placental growth factor mRNA (1.0±0.3-fold change ECMR +/+ +leptin vs 01.3±0.1 ECMR -/- +leptin, P=0.05) in placental tissues. Collectively, these data indicate that ECMR deletion protects pregnant mice from adverse fetal growth and demise in association with increasing NO vascular bioavailability, reducing vascular inflammation and improving placental function in a leptin-infused model of PE.