Long-term aerobic exercise enhances circulating exosomal miR-214-3p to promote endothelial progenitor cell-mediated repair of endothelial damage induced by obesity
Junhao Huang, Peilun Li, Bing Shen, Huiwen Gao, Shen Wang, Pingyu Wang, Weiji Deng, Dongdong Gao, Min Hu
Abstract
• Long-term aerobic exercise enhances the function of endothelial progenitor cells via upregulation of circulating exosomal miR-214-3p, thereby promoting the repair of endothelial dysfunction induced by obesity. • miR-214-3p promotes the function of endothelial progenitor cells directly, by activating COL1A2, and indirectly, through the PTEN-PI3K-Akt pathway. • The myocardium is an important source of the long-term aerobic exercise-induced increase in circulating exosomal miR-214-3p. Exercise training may counteract the detrimental effects of obesity on endothelial function by enhancing the reparative capabilities of endothelial progenitor cells (EPC); however, the underlying mechanisms of exercise-induced EPC-mediated endothelial repair are still unclear. The present study aimed to determine the mechanisms by which exercise-induced circulating exosomes protect against endothelial dysfunction induced by obesity. An 8-week aerobic exercise intervention in both obese human participants and high-fat diet-induced obese rats was conducted. Circulating exosomes were isolated and characterized. microRNA sequencing, molecular biology techniques, and functional assays (including proliferation, migration, and luciferase reporter assays) were employed to identify key exosomal microRNAs and their downstream targets. A microRNA-214-3p (miR-214-3p) knockout rat model was used to validate its role in vivo . Exercise promoted EPC-mediated repair of endothelial damage and upregulated exosomal miR-214-3p in both obese humans and rats, without altering exosome quantity. miR-214-3p enhanced EPC proliferation and migration directly, by upregulating collagen type I alpha 2 chain (COL1A2) expression, and indirectly, through the phosphatase and tensin homolog, phosphatidylinositol 3-kinase, serine/threonine kinase (PTEN-PI3K-Akt) signaling pathway. Knockout of miR-214-3p abolished the exercise-induced improvements in endothelial and EPC functionalities. The myocardium was identified as an important source of the exercise-induced increase in circulating exosomal miR-214-3p. Long-term aerobic exercise promotes endothelial repair in obesity by enriching circulating exosomes with miR-214-3p, which enhances EPC function via the PTEN-PI3K-Akt pathway and direct regulation of COL1A2. These findings reveal a novel exosome-mediated mechanism through which exercise improves vascular health and suggest potential therapeutic strategies for obesity-related endothelial dysfunction.