Study of insulin vascular sensitivity in aortic rings and endothelial cells from aged rats subjected to caloric restriction: Role of perivascular adipose tissue.

The prevalence of metabolic syndrome is dramatically increasing among elderly population. Metabolic syndrome in aged individuals is associated with hyperinsulinemia and insulin resistance both in metabolic tissues and in the cardiovascular system, with this fact being associated with the cardiometabolic alterations associated to this condition. Caloric restriction (CR) improves insulin sensitivity and is one of the dietetic strategies most commonly used to enlarge life and to prevent aging induced cardiovascular alterations. The aim of this study was to analyze the possible beneficial effects of CR in aging-induced vascular insulin resistance both in aortic rings and in primary culture of endothelial cells. In addition, the inflammatory profile of perivascular adipose tissue (PVAT) and its possible role in the impairment of vascular insulin sensitivity associated with aging was also assessed. Three experimental groups of male Wistar rats were used: 3 (3m), 24 (24m) fed ad libitum and 24months old rats subjected to 20% CR during their three last months of life (24m-CR). Aorta rings surrounded or not by PVAT were mounted in an organ bath and precontracted with phenylephrine (10-7.5 M). Changes in isometric tension were recorded in response to cumulative insulin concentrations (10-8 -10-5.5 M) in the presence or absence of L-NAME (10-4 M). Aortic rings and primary aortic endothelial cells were incubated in presence/absence of insulin (10-7 M) and the activation of the PI3K/Akt and MAPK pathways as well as nitrite and nitrates concentrations and the mRNA levels of eNOS, insulin receptor, and GLUT-4 were assessed. CR prevented the aging-induced decrease in the vasodilator response to insulin and the aging-induced increase in the vasoconstrictor response to high insulin concentrations. Changes between 24m and 24m-CR aorta rings were abolished in the presence of L-NAME. CR induced-improvement in insulin vascular sensitivity was related with activation of the PI3K/Akt both in aortic rings and in aortic endothelial cells in response to insulin. CR attenuated the overexpression of iNOS, TNF-α and IL-1β in the PVAT of aged rats although aortic rings surrounded by PVAT from 24m rats showed and increased vasorelaxation in response to insulin compared to aortic rings from 3m and 24m-CR rats. In conclusion, a moderate protocol of CR improves insulin vascular sensitivity and prevents the aging induced overexpression of pro-inflammatory cytokines in PVAT.