Exercise promotes angiogenesis by enhancing endothelial cell fatty acid utilization via liver-derived extracellular vesicle miR-122-5p

Background:Angiogenesis constitutes a major mechanism responsible for exercise-induced beneficial effects.Our previous study identified a cluster of differentially expressed extracellular vesicle microRNAs(miRNAs)after exercise and found that some of them act as exerkines.However,whether these extracellular vesicle miRNAs mediate the exercise-induced angiogenesis remains unknown.Methods:A 9-day treadmill training was used as an exercise model in C57BL/6 mice.Liver-specific adeno-associated virus 8 was used to knock down microRNA-122-5p(miR-122-5p).Human umbilical vein endothelial cells were used in vitro.Results:Among these differentially expressed extracellular vesicle miRNAs,miR-122-5p was identified as a potent pro-angiogenic factor that activated vascular endothelial growth factor signaling and promoted angiogenesis both in vivo and in vitro.Exercise increased circulating levels of miR-122-5p,which was produced mainly by the liver and shuttled by extracellular vesicles in mice.Inhibition of circulating miR-122-5p or liver-specific knockdown of miR-122-5p significantly abolished the exercise-induced pro-angiogenic effect in skeletal muscles,and exerciseimproved muscle performance in mice.Mechanistically,miR-122-5p promoted angiogenesis through shifting substrate preference to fatty acids in endothelial cells,and miR-122-5p upregulated endothelial cell fatty-acid utilization by targeting 1-acyl-sn-glycerol-3-phosphate acyltransferase(AGPAT1).In addition,miR-122-5p increased capillary density in perilesional skin tissues and accelerated wound healing in mice.Conclusion:These findings demonstrated that exercise promotes angiogenesis through upregulation of liver-derived extracellular vesicle miR-122-5p,which enhances fatty acid utilization by targeting AGPAT1 in endothelial cells,highlighting the therapeutic potential of miR-122-5p in tissue repair.