Effects of Exercise on PVAT-Derived Exosomes in the Modulation of Vascular Function in Obese Mice

This study investigated whether perivascular adipose tissue (PVAT)-derived exosomal miRNAs contribute to exercise-induced improvement of vascular function in obesity. Male C57BL/6J mice were assigned to normal diet control (NC), high-fat diet control (HC), or high-fat diet with exercise (HE) groups. After 20 weeks of high-fat feeding, obese mice in the HE group underwent treadmill exercise for 8 weeks. Vascular contraction and relaxation were assessed in the presence or absence of PVAT-derived exosomes, which were further analyzed using a whole transcriptome sequencing. In vitro, vascular smooth muscle cells (VSMCs) were incubated with exosomes secreted from 3T3-L1 adipocytes (transfected with a miR-122-5p mimic) to evaluate phenotypic gene expression and migration. Compared with HC, arteries incubated with PVAT-conditioned medium from HE mice showed significantly reduced maximal constriction and improved endothelium-independent relaxation, whereas these effects were attenuated after removal of exosomes (P < 0.05). Exercise markedly altered the miRNA profile of PVAT-derived exosomes. Among these miRNAs, miR-122-5p was increased in obesity but decreased after exercise (P < 0.05). Exosomes enriched with miR-122-5p promoted VSMC migration and shifted phenotype gene expressions (down-regulated contractile ACTA2 and TAGLN and up-regulated synthetic SPP1; P < 0.05). This study is the first to show that PVAT-derived exosomes critically contribute to vascular function in obesity after exercise intervention. A unique exosomal miRNA signature may represent a potential regulatory mechanism underlying exercise-mediated vascular restoration, with miR-122-5p identified as a candidate molecule involved in triggering VSMC synthetic phenotype switching.