Leptin‐induced Endothelial Dysfunction is Mediated by Endothelial Mineralocorticoid Receptor Activation in Premenopausal and Pregnant Females
Authors: Faulkner Jessica L , Kennard Simone , Antonova Galina , Jaffe Iris Z , Patel Vijay , Belin de Chantemele Eric J 
Published: June 2021

Obesity is the most significant risk factor for diabetes and cardiovascular diseases. Clinical evidence indicates that mineralocorticoid receptor (MR) antagonists are more efficacious for cardiovascular treatment in obese and diabetic females than in males, however, the origin of this sex‐specific effect is unknown. Our lab previously showed that adipocyte‐derived leptin is required for endothelial dysfunction (EnDn) in obese diabetic female mice, which develops via leptin‐induced aldosterone secretion and subsequent MR activation. We further showed that female mice are more sensitive to aldosterone‐induced EnDn than males via an as yet unknown endothelial factor. We hypothesized that females express higher endothelial MR (ECMR) expression than males which predisposes females to obesity‐associated EnDn. RT‐PCR analysis in isolated aortic endothelial cells of Balb/C lean mice revealed a higher MR mRNA expression in females compared to males (2.9±0.5‐fold, P<0.05), however, no such difference was observed in non‐endothelial cells (0.1±0.3‐fold). Similarly, human endothelial cells from female patients exhibited higher ECMR mRNA (2.0±0.2 fold, P<0.05) and protein expression in endothelial cells (0.35±0.1 male vs 1.15±0.2 female ratio/actin, P<0.05) compared to those from males. Obesity and hyperglycemia in Agouti female mice was associated with a further increase in ECMR mRNA expression (2.65±0.4 fold from wild‐type female, P<0.05). Female sex‐hormone suppression (ovariectomy) decreased ECMR mRNA expression in female mice (−0.8±0.2−fold from sham, P<0.05), which was restored by progesterone treatment (−0.1±0.1‐fold from sham). Progesterone dose‐dependently increased ECMR protein expression in human endothelial cells in vitro (0.1–100 ng/ml range, P<0.05), indicating that progesterone induces ECMR. To assess a potential role for ECMR in leptin‐mediated EnDn we measured aorta relaxation responses to acetylcholine ex vivo (10−9–10−5M concentration). Leptin infusion (0.9mg/kg/day, 7 days) induced EnDn in intact ECMR female mice (P<0.05), however, specific deletion of ECMR protected female mice from leptin‐induced EnDn indicating that leptin‐mediated EnDn is mediated by ECMR activation in females. We further discovered that ECMR mRNA increased with circulating progesterone levels in pregnant mice (9.2±0.2‐fold from nonpregnant, P<0.05), indicating a potential role for ECMR in obesity‐associated cardiovascular diseases of pregnancy. Our preliminary data indicate that leptin infusion impairs EnDn in pregnant mice both compared to virgin leptin‐infused female and normal pregnant mice (P<0.05). Collectively, these data indicate that progesterone increases ECMR expression in female mice which predisposes obese and pregnant female mice to leptin‐induced EnDn. Therefore, MR antagonists may be more efficacious for cardiovascular treatment in obese premenopausal women via ECMR inhibition.Support or Funding InformationNIH 1R01HL130301‐01, AHA 16IRG27770047, AHA 17POST33660678, NIH 5F32HL136191‐02.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.