1. Exercise promotes angiogenesis by enhancing endothelial cell fatty acid utilization via liver-derived extracellular vesicle miR-122-5p
- Author
-
Yong Zhao, Mengya Feng, Feng Gao, Yan Wang, Xue Dang, Xing Zhang, Jie Wu, Hongyan Yang, Jia Li, Jiankang Liu, Lin Zhao, Jing Lou, Guiling Wu, and Changhong Shi
- Subjects
Vascular Endothelial Growth Factor A ,Gene knockdown ,Angiogenesis ,Fatty Acids ,Neovascularization, Physiologic ,Physical Therapy, Sports Therapy and Rehabilitation ,Extracellular vesicle ,Umbilical vein ,Cell biology ,Mice, Inbred C57BL ,Endothelial stem cell ,Vascular endothelial growth factor ,Extracellular Vesicles ,Mice ,MicroRNAs ,chemistry.chemical_compound ,Liver ,Downregulation and upregulation ,chemistry ,Physical Conditioning, Animal ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Orthopedics and Sports Medicine ,Wound healing - Abstract
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 exercise-improved 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 use 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 use by targeting AGPAT1 in endothelial cells, highlighting the therapeutic potential of miR-122-5p in tissue repair.
- Published
- 2022