Antagonistic effects of mineralocorticoid receptor (MR) blockade on the vascular reactivity of male and female leptinsensitized mice

Abstract

Leptin is an adipocyte‐derived hormone secreted in excess in obesity. Due to its ability to increase sympathetic tone, and aldosterone (Aldo) levels, leptin is viewed as a key factor involved in obesity‐related cardiovascular disease (CVD). Females secrete 4 times more leptin than males. Whether females are more sensitive to CVD than males is unknown. We hypothesize that excessive leptin levels trigger an increased Aldo secretion and exaggerated CVD in females. To test this hypothesis we analyzed the cardiovascular phenotype of mice hypersensistive to leptin due to the deletion of PTP1B, a molecular brake on leptin signaling. Irrespective of genotypes, leptin levels were 4 times higher in females. Aldo levels were increased in females and further enhanced with the deletion of PTP1B. Sex and genotype synergistically increases adrenals weight and Aldo synthase expression without effects on angiotensin II levels. Although PTP1B deficiency similarly increases blood pressure in both sexes, it only triggers an endothelial dysfunction in females that was restored by MR blockade. Vascular contractility to phenylephrine, reduced in KO males, was not affected in KO females. MR blockade restored it in males and reduced it in females. This suggests that females are more sensitive to leptin‐mediated CVD than males but also that MR antagonists have sex‐specific effects justifying the need for gender‐based therapy.