Spironolactone ameliorates the endothelial dysfunction induced by visceral adipose tissue in obese female mice exposed to early life stress.

Previously, we have shown that female mice exposed to maternal separation and early weaning (MSEW), a mouse model of early life stress, display an exacerbated obesogenic response to a hypercaloric diet via a mechanism that most likely involves the mineralocorticoid receptor (MR). This study investigated whether perivascular adipose tissue-derived factors influence vascular endothelial function in obese female MSEW mice using the MR antagonist spironolactone in vivo. C57BL/6J mice pups were subjected to MSEW or control rearing. At weaning, female mice were placed on a high-fat diet for 20 wk and treated with vehicle or spironolactone (100 mg/kg/day) for two additional weeks. Mice were then euthanized, thoracic aortas were isolated and cleaned to assess endothelial function in aortic rings preincubated with either DMEM, or explant media from either perivascular adipose tissue (PVAT) or mesenteric adipose tissue (MESAT) incubated in DMEM (2 h, 37°C). MSEW did not influence acetylcholine (ACh)-induced maximal relaxation in isolated rings of vehicle-treated mice preincubated with DMEM or PVAT explant media. However, preincubation with MESAT explant media impaired relaxation only in MSEW mice. Overall, spironolactone improved vascular relaxation in isolated rings preincubated with either type of adipose tissue explant; however, this effect was enhanced in rings from MSEW mice preincubated with their MESAT explant media. Taken together, these findings suggest that MESAT-derived endocrine and inflammatory mediators promote endothelial dysfunction in obese female mice exposed to MSEW, whereas spironolactone ameliorates this effect.NEW & NOTEWORTHY Adverse childhood experiences (ACEs) are associated with increased cardiometabolic disease risk, where women display a greater visceral adipose tissue expansion. This study identifies potential visceral adipose tissue-specific factors that contribute to vascular dysfunction, provides mechanistic insight into sex-specific cardiometabolic vulnerability, and highlights MR signaling as a potential therapeutic target to reduce health disparities linked to childhood adversity.