Hypoxic Exosomal miRNAs From Skeletal Muscle Enhances Angiogenesis in Lower Limb Ischemia

Lower limb ischemia in diabetic patients results in poor collateral circulation and a high risk of amputation. Skeletal muscle cells release exosomes that are believed to regulate angiogenesis; however, the underlying mechanisms remain unclear. This study examined the effects of exosomes derived from skeletal muscle cells on angiogenesis. Exosomes derived from human skeletal muscle cells (HSMCs) were isolated and characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. The effects of these exosomes on endothelial cells were evaluated through proliferation, migration, and tube formation assays. Differential expression of miRNAs between hypoxic and normoxic exosomes was identified through sequencing, with a focus on novel_196 and its role in regulating angiogenesis. Hypoxic skeletal muscle cells-derived exosomes significantly enhanced endothelial cell proliferation, migration, migration, and tube formation while reducing apoptosis. Sequencing analysis revealed 11 differentially expressed microRNAs, with novel_196 being notably downregulated under hypoxic conditions. The overexpression of novel_196 inhibited angiogenesis by targeting the FGF2 and p-AKT pathways. The findings indicate that targeting novel_196 under hypoxic conditions may enhance angiogenesis, improve collateral circulation, and reduce the likelihood of amputation in individuals with diabetic ischemic foot.