Endothelial mineralocorticoid receptor deletion ablates leptin‐induced cardiovascular and fetal growth preeclampsia characteristics in pregnant mice

Abstract

Obesity increases the risk for preeclampsia (PE), a hypertensive syndrome of pregnancy characterized by placental ischemia. Obese PE patients demonstrate increases in plasma leptin levels in midgestation due to increased placental leptin production. We have shown that pregnancy increases endothelial mineralocorticoid receptor (ECMR) expression and that ECMR mediates leptin-induced endothelial dysfunction and hypertension in nonpregnant females. We therefore hypothesized that ECMR deletion protects from the development endothelial dysfunction, hypertension and fetal growth restriction in pregnant leptin-infused mice. Pregnant ECMR+/+ (WT) and ECMR-/- (KO) littermate mice were infused with vehicle or leptin (N=4-6/group) by osmotic minipump (0.9mg/kg/day, s.c.) from GD11-18 and thoracic aortas assessed for vascular function by wire myography. Separate groups (N=1-2/group) were implanted with radiotelemeters for systolic blood pressure (BP) measurement. Leptin decreased pup weight (0.86±0.04g WT vs 0.52±0.11g WT+lep, *P<0.05) and placental efficiency (9.7±0.7 WT vs 7.9±0.6 WT+lep, pup/placenta weight ratio, *P<0.05) indicating fetal growth restriction. ECMRdeletion prevented leptin-mediated decreases in pup weight (0.91±0.06g KO vs 1.0±0.07g KO+lep) and placental efficiency (9.6±0.5 KO vs 9.4±1.2 KO+lep). Preliminary data shows that prior to leptin infusion (GD8-11) all groups demonstrated similar BP and circadian rhythm of BP. Leptin infusion increased BP and ablated circadian rhythm (GD11-18, 114 mmHg WT vs 137 mmHg WT+lep), however, ECMR deletion blunted leptin-induced BP increases (112 KO mmHg vs 120 mmHg KO+lep) and preserved circadian rhythm. Leptin infusion reduced endothelial function (acetylcholine-mediated relaxation) in aortas of WT, but not KO, pregnant mice (2-way ANOVA, repeated measures, *P<0.05). Relaxation to acetylcholine with LNAME showed restoration of endothelial function in KO+lep mice was NO-dependent. In addition, ECMR deletion protected pregnant mice from leptin-induced increases in vascular α1 receptor-mediated constriction (phenylephrine) (*P<0.05). Endothelial-independent relaxation to sodium nitroprusside was similar across all groups. Moreover, ECMR deletion protected from leptin-mediated increases in placental mRNA expression of: sFlt-1 (WT+leptin: 1.2±0.03-fold from WT, *P<0.05, KO+leptin: 1.1±0.1-fold change from KO), HIF1α (WT+leptin: 1.6±0.1-fold, P=0.09, KO+leptin: 1.5±0.2-fold) and galectin 3 (WT+leptin: 3.2±0.5-fold, *P<0.05, KO+leptin: 0.8±0.1-fold). Collectively, these data indicate that ECMR deletion decreases BP, improves vascular function and placental function in association with increased vascular NO bioavailability and fetal growth in an obesity-associated, leptin-infusion model of PE.