Prophylactic exercise-derived circulating exosomal miR-125a-5p promotes endogenous revascularization after hindlimb ischemia by targeting endothelin converting enzyme 1.
Prophylactic exercise-derived circulating exosomal miR-125a-5p promotes endogenous revascularization after hindlimb ischemia by targeting endothelin converting enzyme 1.
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预防性运动源性循环外泌体 miR-125a-5p 通过靶向内皮素转换酶 1 促进后肢缺血后内源性血运重建
DOI：
10.3389/fcvm.2022.881526
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发表时间：
2022
影响因子：
3.6
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中科院分区：
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预防性运动可改善患有严重缺血性疾病的患者的临床结果。此前的研究表明，运动可以改变循环中外切体的数量或含量。然而，前驱运动衍生的循环外切体(Exe-Exo)在缺血性疾病中的作用知之甚少。因此，我们旨在探讨Exe-Exo在外周动脉疾病内源性血管重建和灌流恢复中的作用和机制。我们首先确定，在单侧股动脉结扎(FAL)后7、14和21天，4周的前驱跑步机运动可以促进血流灌注恢复，但在结扎后立即没有效果。然后，局部肌肉递送Exe-Exo促进动脉生成、血管生成和灌流恢复，这可以被GW4869所阻断，GW4869是一种公认的抑制外切体释放的药理药物。这表明Exe-Exo介导了运动诱导的血管重建。在体外，Exe-Exo促进内皮细胞的增殖、迁移和管状形成。此外，通过外体miRNA测序和RT-qPCR验证，我们确定miR-125a-5p是一个新的出血因子。抑制miR-125a-5p可在体内和体外消除exe-exo的有益作用。从机制上讲，这些运动带来的好处归因于外体miR-125a-5p下调ECE1的表达，以及随后激活AKT/eNOS下游信号通路。具体地说，通过荧光原位杂交，骨骼肌可能是运动诱导的外体miR-125a-5p的主要组织来源。内源性循环外体miR-125a-5p通过靶向ECE1和激活AKT/eNOS下游信号通路促进运动诱导的血管重建。鉴定外体miR-125a-5p是一种新的激动素，并强调其在预防和治疗外周动脉疾病中的潜在治疗作用。运动诱导的循环外切体促进肢体缺血后动脉生成和血管生成的机制。4周运动训练主要增加内收肌miR-125a-5p的表达，并将miR-125a-5p转运到运动源性外切体。这些miR-125a-5p丰富的外切体通过靶向ECE1和激活AKT/eNOS信号通路，被输送到血管内皮细胞，促进股动脉结扎后的血液灌流恢复。
Prophylactic exercise improves clinical outcomes in patients experiencing severe ischemic diseases. Previous studies have shown that exercise could alter the amount or content of circulating exosomes. However, little is known about the role of precursory exercise-derived circulating exosomes (Exe-Exo) in ischemic diseases. We therefore aimed to explore the function and mechanism of Exe-Exo in endogenous revascularization and perfusion recovery in peripheral arterial disease. We first determined that 4 weeks of precursory treadmill exercise improved perfusion recovery on days 7, 14 and 21 after unilateral femoral artery ligation (FAL) but had no effect immediately after ligation. Then, local muscle delivery of Exe-Exo promotes arteriogenesis, angiogenesis and perfusion recovery, which could be abolished by GW4869, a well-recognized pharmacological agent inhibiting exosome release. This suggests that Exe-Exo mediated exercise-induced revascularization. In vitro, Exe-Exo enhanced endothelial cell proliferation, migration and tube formation. In addition, we identified miR-125a-5p as a novel exerkine through exosomal miRNA sequencing and RT-qPCR validation. Inhibition of miR-125a-5p abrogated the beneficial effects of Exe-Exo both in vivo and in vitro. Mechanistically, these exercise-afforded benefits were attributed to the exosomal miR-125a-5p downregulation of ECE1 expression and the subsequent activation of the AKT/eNOS downstream signaling pathway. Specifically, skeletal muscle may be a major tissue source of exercise-induced exosomal miR-125a-5p via fluorescence in situ hybridization. Endogenous circulating exosomal miR-125a-5p promotes exercise-induced revascularization via targeting ECE1 and activating AKT/eNOS downstream signaling pathway. Identify exosomal miR-125a-5p as a novel exerkine, and highlight its potential therapeutic role in the prevention and treatment of peripheral arterial disease. Proposed mechanisms by which exercise-induced circulating exosomes promote arteriogenesis and angiogenesis after lower limb ischemia. Four weeks of exercise training mainly increased miR-125a-5p expression in adductor muscles and cargoes into exercise-derived exosomes. These miR-125a-5p-enriched exosomes were delivered to endothelial cells and enhanced blood perfusion recovery after femoral artery ligation by targeting ECE1 and activating the AKT/eNOS signaling pathway.