MICE EXPOSED TO EARLY LIFE STRESS SHOW SEX-SPECIFIC EFFECT OF WATOKINES ON ENDOTHELIAL FUNCTION

Abstract

Abstract Objective: The aim of this study was to determine the effects of Maternal Separation and Early Weaning (MSEW), a mouse model of early life stress, on leptin production from different fat depots and the capacity of fat conditioned media to modulate the endothelial function of aortic ring in a sex-specific manner. Design and method: At weaning, control and MSEW mice were fed a high fat (HF, 16-weeks, 60% Kcal from fat). In one subset of mice, white adipose tissue (WAT) was collagenase-digested and preadipocytes counted by flow cytometry. In another subset of mice, ∼50 mg of freshly-isolated WAT was incubated in DMEM + 2% fatty acid free BSA (1 hour, 37°C) to measure leptin levels. Further, acetylcholine-induced relaxation in aortic rings from healthy mice (16-week-old fed a regular chow) was assessed to test how different fat depots media explants can modulate the endothelial function independently of the effects of MSEW on the vascular wall. Results: MSEW females showed a 20% increase in preadipocyte number in visceral-WAT vs. control (p < 0.05). Fat-derived leptin secretion was similar between control and MSEW mice fed a low fat diet. However, HF increased leptin secretion in subcutaneous-WAT from male MSEW mice and visceral-WAT from female MSEW mice (p < 0.05). Similarly, HF increased leptin mRNA in subcutaneous-WAT from male MSEW mice and visceral-WAT from female MSEW mice (p < 0.05). Baseline vascular relaxation (48 ± 3 % relaxation at 5.5 x10–5mmol/L) was similarly impaired when aortic rings were incubated with perivascular adipose tissue (PVAT) media explants from female MSEW and control mice (25 ± 4 and 32 ± 2 % relaxation, respectively). However, rings incubated with visceral-WAT from female MSEW mice showed greater impairment of the vascular relaxation compared to controls (15 ± 3 and 29 ± 2 % relaxation, respectively, p < 0.05). Male MSEW mice also displayed endothelial dysfunction in isolated rings; however, PVAT and visceral-VAT media explant induced a protective effect on endothelial function. Conclusions: Taken together this data indicates that there is a sex and depot-specific release of WATokines that could be an important factor modulating the vascular function in mice exposed to early life stress.