Early life stress induces MR-dependent increases in circulating and adipose tissue-derived IL17a in female mice fed a high fat diet
Authors: Turner Meghan , Ahmed Nermin , Cincinelli Cole , Loria Analia 
Published: May 2023

Increased levels of pro-inflammatory cytokine Interleukin 17a (IL17) from adipose tissue have been linked to hypertension and metabolic syndrome in both humans and mice. Studies have demonstrated a causal role for IL17 in vascular dysfunction in angiotensin II-induced hypertension. IL17 secretion is modulated by T-helper 17 (Th17) lymphocytes downstream of mineralocorticoid receptor (MR) activation on dendritic cells (DC). In models of obesity, Th17 are known to infiltrate and expand in adipose tissue (AT). Perivascular AT (PVAT) directly modulates vascular function via secretion of adipose-derived factors. Previously, we have shown that female mice exposed to maternal separation and early weaning (MSEW), a model of early life stress, display exacerbated obesogenic response to high fat diet feeding (HF) and metabolic syndrome-like phenotype that can be attenuated by the chronic treatment with MR antagonist spironolactone. Therefore, this study aimed to determine if there is an MR-dependent role of IL17 from PVAT on endothelial function in obese female MSEW mice. Female MSEW and control (C) mice were weaned onto HF (60 % Kcal from fat) for 20 weeks, then randomized to receive either vehicle (50% Ora swift in drinking water) or spironolactone (100 mg/kg/d in vehicle) treatment for 2 weeks. Upon euthanasia, plasma was to measure cytokines using a milliplex assay (n=5 per group). Thoracic aortas were then isolated and cleaned for vascular reactivity studies, and aortic and mesenteric perivascular adipose tissue (aPVAT and mPVAT, respectively) was collected in DMEM (2% BSA, 2-hour incubation, 37C). Cumulative concentration response (CCR) curves were performed for acetylcholine (Ach, 10-5 to 10-9 M) and sodium nitroprusside (SNP, 1x10-6 to 1x10-14 M) after pre-constriction with serotonin (2×10-3 M, 5 ul). Maximal vascular relaxation of aortic rings was similar between groups, however, preincubation with mPVAT media explant impaired vascular relaxation only in MSEW mice (p<0.05), while maximal relaxation was improved in the spironolactone treated MSEW mice. Compared to controls, MSEW mice showed increased plasma levels of circulating INFg (14.5 ±5.9 MSEW vs. 35.2 ± 7.7 C, p<0.05), TNFa (29.6 ± 8.2 MSEW vs. 118.2±29.1 C, p<0.05) and IL17 (65.8 ±16.8 MSEW vs. 181.9 ± 39.4 C, p<0.05). This increase in MSEW plasma was blunted by spironolactone treatment (95.5±24.5 VEH vs 105.1±21.4 MSEW, p<0.05). Moreover, the levels of IL17 in PVAT media explant showed similar pattern to plasma levels, suggesting that infiltrating cells in AT may be contributing to impair vascular function. Further investigation is needed to pinpoint the role of Th17 and DC activation in fat contributing to vascular endothelial dysfunction in obese female mice exposed to early life stress. Naturally, mPVAT is not in contact with aorta but could have a detrimental effect in the resistance vessels endothelium. HL135158 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.