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.

Deformation and phase transformation mechanisms of 40Cr10Si2Mo steel during hot compression

Thermo-mechanical experiments on martensitic heat-resistant 40Cr10Si2Mo steel were conducted using a Gleeble simulator in temperature and strain rate ranges of 1073–1373 K and 0.1–20 s^(-1),respectively.Processing maps were developed and correlated with deformed microstructures based on the dynamic material model theory.The analysis of the maps revealed that both applied temperature and strain rate had significant effects on the power dissipation efficiency and flow instability of the steel alloy.Electron backscatter diffraction analysis was also implemented to study the effect of deformation conditions on martensitic morphology.The results showed that higher temperatures and strain rates led to a fine martensitic packet,and the martensite lath increased in width at high temperatures.Two deformation domains,which exhibit different recrystallization processes,were recognized.The discontinuous dynamic recrystallization(DRX)mechanism in the low strain rate domain was characterized by the migration and growth of high-angle grains during straining.In contrast,in the high strain rate domain,the development of new grain boundaries is primarily associated with the deformation microbands in the low-temperature deformation domain.As the temperature increased,the high dislocation density accelerated the migration of the grain boundaries.Furthermore,the DRX mechanism changed from continuous DRX to post-DRX.This change in the DRX mechanism type was attributed to the time during which the sample remained high temperature after deformation.