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Background: Patients with preeclampsia demonstrate increases in placental leptin production in midgestation, and an associated increase in late gestation plasma leptin levels. The consequences of mid-late gestation increases in leptin production in pregnancy is unknown. Our previous work indicates that leptin infusion induces endothelial dysfunction in nonpregnant female mice via leptin-mediated aldosterone production and endothelial mineralocorticoid receptor (ECMR) activation, which is ablated by ECMR deletion. Therefore, we hypothesized that leptin infusion in mid-gestation of pregnancy induces endothelial dysfunction and hypertension, hallmarks of clinical preeclampsia, which are prevented by ECMR deletion. Methods: Leptin was infused via miniosmotic pump (0.9 mg/kg per day) into timed-pregnant ECMR-intact (WT) and littermate-mice with ECMR deletion (KO) on gestation day (GD)11-18. Results: Leptin infusion decreased fetal weight and placental efficiency in WT mice compared with WT+vehicle. Radiotelemetry recording demonstrated that blood pressure increased in leptin-infused WT mice during infusion. Leptin infusion reduced endothelial-dependent relaxation responses to acetylcholine (ACh) in both resistance (second-order mesenteric) and conduit (aorta) vessels in WT pregnant mice. Leptin infusion increased placental ET-1 (endothelin-1) production evidenced by increased PPET-1 (preproendothelin-1) and ECE-1 (endothelin-converting enzyme-1) expressions in WT mice. Adrenal aldosterone synthase ( CYP11B2 ) and angiotensin II type 1 receptor b ( AT1Rb ) expression increased with leptin infusion in pregnant WT mice. KO pregnant mice demonstrated protection from leptin-induced reductions in pup weight, placental efficiency, increased BP, and endothelial dysfunction. Conclusions: Collectively, these data indicate that leptin infusion in midgestation induces endothelial dysfunction, hypertension, and fetal growth restriction in pregnant mice, which is ablated by ECMR deletion.

Placental ischemia, an initiating event of preeclampsia (PE), increases plasma leptin levels. We recently developed a model of midgestation (gestation day (GD)11-18) leptin infusion mimicking the midgestation rise in leptin levels of PE patients. Our previous work demonstrates that deletion of endothelial mineralocorticoid receptors (ECMR) improves markers of vascular dysfunction in leptin-infused female mice. We hypothesized vascular function improvement with ECMR deletion ablates hypertension and fetal growth restriction in pregnant leptin-infused mice. Pregnant ECMR +/+ (WT) and ECMR -/- (KO) mice were infused with vehicle or leptin by osmotic pump (lep, 0.9mg/kg/day, s.c.) on GD11-18 while implanted with radiotelemeters for conscious blood pressure (BP) measurement and wire myography of thoracic aorta and 2 nd order mesenteric arteries at GD18 (*=P

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.