PDF(Pubmed)
Abstract：
MicroRNAs (miRs) regulate physiological and pathological processes, including ischemia-induced angiogenesis and neovascularization. They can be transferred between cells by extracellular vesicles (EVs). However, the specific miRs that are packaged in EVs released from skeletal muscles, and how this process is modulated by ischemia, remain to be determined. We used a mouse model of hindlimb ischemia and next generation sequencing (NGS) to perform a complete profiling of miR expression and determine the effect of ischemia in skeletal muscles, and in EVs of different sizes (microvesicles (MVs) and exosomes) released from these muscles. Ischemia significantly modulated miR expression in whole muscles and EVs, increasing the levels of several miRs that can have pro-angiogenic effects (angiomiRs). We found that specific angiomiRs are selectively enriched in MVs and/or exosomes in response to ischemia. In silico approaches indicate that these miRs modulate pathways that play key roles in angiogenesis and neovascularization, including HIF1/VEGF signaling, regulation of actin cytoskeleton and focal adhesion, NOTCH, PI3K/AKT, RAS/MAPK, JAK/STAT, TGFb/SMAD signaling and the NO/cGMP/PKG pathway. Thus, we show for the first time that angiomiRs are selectively enriched in MVs and exosomes released from ischemic muscles. These angiomiRs could be targeted in order to improve the angiogenic function of EVs for potential novel therapeutic applications in patients with severe ischemic vascular diseases.
摘要：
microRNAs（miRs）调节生理和病理过程，包括缺血诱导的血管生成和新生血管形成。它们可以通过细胞外囊泡(EV)在细胞之间转移。然而,包装在从骨骼肌释放的电动汽车中的特定miRs，以及缺血如何调节这个过程，仍有待确定。我们使用后肢缺血和下一代测序（NGS）的小鼠模型来进行miR表达的完整谱分析，并确定缺血在骨骼肌中的作用，以及从这些肌肉释放的不同大小的EV（微囊泡（MV）和外泌体）。缺血显著调节整个肌肉和电动汽车的miR表达，增加可具有促血管生成作用的几种miR的水平(angiomiRs)。我们发现,响应于局部缺血,特异性血管瘤受体选择性地富集在MV和/或外泌体中。计算机模拟方法表明，这些miR调节在血管生成和新血管形成中起关键作用的途径，包括HIF1/VEGF信号，肌动蛋白细胞骨架和粘着斑的调节，NOTCH,PI3K/AKT,RAS/MAPK,JAK/STAT,TGFb/SMAD信号传导和NO/cGMP/PKG通路。因此，我们首次显示血管miRs在缺血肌肉释放的MV和外泌体中选择性富集。这些血管瘤可以作为目标，以改善EV的血管生成功能，用于严重缺血性血管疾病患者的潜在新型治疗应用。
