Suppression of Aldosterone Production via High Salt Diet and Deficiency in Endothelial Mineralocorticoid Receptors Prevents Leptin‐Mediated Endothelial Dysfunction Exclusively in Female Mice
Authors: Faulkner Jessica L , Bruder‐Nascimento Thiago , Jaffe Iris , de Chantemele Eric Belin 
Published: November 2023

Worldwide rates of obesity are higher in women than in men. Obesity abolishes the protective effects of female sex hormones from cardiovascular diseases (CVD) and, therefore, greatly contributes to morbidity and mortality in women. Previous studies from our lab suggest a sex‐discrepancy in the role of the adipocyte‐derived hormone leptin in CVD development. We have shown that leptin induces activation of the aldosterone‐Mineralocorticoid Receptor (MR) pathway, which appears to be a key mediator of leptin‐induced CVD in female mice, but not in males. The current study tested the hypothesis that suppression of aldosterone production via a high salt diet prevents leptin‐mediated endothelial dysfunction and hypertension in female mice, and further, that deficiency in endothelial MR expression in female mice prevents leptin‐induced endothelial dysfunction. This hypothesis was tested with two protocols. In the 1st, carotid radiotelemeters were implanted in Balb/C male and female mice at 10 weeks of age and blood pressure was measured for 7 days. Continuous infusion of leptin (0.9mg/kg/day via miniosmotic pump) concurrent with a normal or high salt (4%NaCl) diet (HSD) regimen was then implemented for 7 days. Reactivity to acetylcholine, phenylephrine and sodium nitroprusside in excised aortas was analyzed at terminus. In the 2nd protocol, we administered leptin as in the 1st protocol in female endothelial cell‐specific MR knockout (ECMR) mice for 7 days followed by analysis of vascular reactivity in excised aortas. Neither leptin nor leptin+HSD altered mean arterial pressure in male (104.9±3.7 and 101.5±3.5mmHg, respectively) or female (105.5±3.7 and 100.3±2.2mmHg, respectively) mice compared to control male (104.8±1.1mmHg) and female (102.9±1.3mmHg) mice. However, leptin treatment in female mice significantly impaired endothelial function compared to control (P<0.05), which was reflected by reduced vascular relaxation to acetylcholine. HSD abolished leptin‐induced endothelial dysfunction in female mice exclusively (P<0.05). No differences in endothelial function were observed between control, leptin‐treated or leptin+HSD in male mice. No differences in responses to phenylephrine or sodium nitroprusside were observed between groups. In the 2nd protocol, wild‐type littermate control female mice developed impaired endothelial function in response to leptin when compared to untreated controls (P<0.05). Endothelial MR deletion prevented leptin‐mediated endothelial dysfunction in female mice. No significant differences were observed in response to phenylephrine or sodium nitroprusside between groups. In summary, both administration of a high salt diet and deficiency in endothelial MR expression prevent leptin‐mediated endothelial dysfunction in female mice. In conclusion, these data indicate that leptin‐mediated cardiovascular disease is dependent on aldosterone production and on endothelial MR activation in female mice.

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NIH: 1R01HL130301‐01 and AHA: 16IRG27770047