Perivascular adipose tissue dysfunction and inflammation in obesity: the role of mineralocorticoid receptors

Abstract

Obesity prevalence has been increased and high body mass index is an important risk factor for cardiovascular diseases (CVD) which are responsible for high mortality worldwide. An impaired perivascular adipose tissue (PVAT) anticontractile function associated with PVAT inflammation have been demonstrated to contribute for vascular injury in obesity. However, the mechanisms involved in the PVAT dysfunction in obesity are not completely understood. Higher plasma levels of aldosterone have been shown in obese individual. In addition, mineralocorticoid receptor (MR) antagonism improves endothelial function and inflammation in type 2 diabetes, suggesting a potential role for MR activation on the obesity-induced vascular injury. In the present project, we hypothesized that MR activation could be involved in the obesity-induced inflammatory response and anticontractile dysfunction of PVAT. It is known that MR is functionally expressed in cells of vascular wall such as immune cells and endothelial cells (EC). MR activation in EC stimulates leukocyte adhesion and M1 polarization of macrophage, raising MR signaling in these cells as a relevant target for PVAT dysfunction during obesity. For the purpose of the present study, mice fed a high-fat diet will be treated with the MR antagonist spironolactone. In addition, mice lacking MR in EC (EC-MR-/-) or in myeloid cells (MO-MR-/-) fed chow or a high-fat diet will be used to evaluate cell-specific role of MR activation in EC and macrophages. Mesenteric resistance arteries (MRA) and respective PVAT will be harvested. Anticontractile function of PVAT will be investigated in MRA in the presence and absence PVAT. PVAT leucocyte infiltration, anti- and pro-inflammatory cytokines, macrophage polarization profile and oxidative stress will be evaluated. (AU)