Autophagy promotes directed migration of HUVEC in response to electric fields through the ROS/SIRT1/FOXO1 pathway
Autophagy promotes directed migration of HUVEC in response to electric fields through the ROS/SIRT1/FOXO1 pathway
复制标题
自噬通过 ROS/SIRT1/FOXO1 途径促进 HUVEC 响应电场的定向迁移
DOI：
10.1016/j.freeradbiomed.2022.09.020
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发表时间：
2022-10-02
影响因子：
7.4
通讯作者：
Zhang，Xuanfen
中科院分区：
文献类型：
--
作者：
Li，Yi;Jiang，Xupin;Zhang，Xuanfen
内源性电场(EFS)通过引导内皮细胞(ECs)定向迁移促进血管生成已被证实，但其潜在机制尚不清楚。最近的研究表明，血管生成中内皮细胞的定向迁移与自噬有关，而自噬可被EFS增强。我们推测，在血管生成过程中，自噬可能参与了EFS引导的内皮细胞迁移。在此，我们证明了EFS通过增强自噬诱导人脐静脉内皮细胞(HUVEC)向阴极迁移。通过沉默自噬相关基因(ATG)5来基因消融自噬，可以取消EFS引导的HUVEC的迁移，这表明自噬对于EFS引导的细胞迁移是绝对必要的。在机制上，我们通过增强沉默信息调节因子2相关酶1(SIRT1)/叉头盒蛋白O1(FOXO1)信号，确定细胞内活性氧(ROS)是EFS触发的自噬的关键介质。ROS清除或SIRT1基因敲除都消除了EFS触发的HUVEC自噬。进一步的研究表明，SIRT1促进FOXO1去乙酰化，促进其核积累和转录活性，从而激活EFS处理的HUVECs的自噬。综上所述，我们的研究证实了自噬在EFS诱导的HUVECs通过ROS/SIRT1/FOXO1途径定向迁移中的关键作用，并为血管生成提供了新的理论基础。
Endogenous electric fields (EFs) have been confirmed to facilitate angiogenesis through guiding directional migration of endothelial cells (ECs), but the underlying mechanisms remain obscure. Recent studies suggest that the directed migration of ECs in angiogenesis is correlated with autophagy, and the latter of which could be augmented by EFs. We hypothesize that autophagy may participate in the EFs-guided migration of ECs during angiogenesis. Herein, we showed that EFs induced human umbilical vein endothelial cells (HUVEC) migration toward the cathode with enhanced autophagy. Genetic ablation of autophagy by silencing the autophagy-related gene (Atg) 5 abolished the EFs-directed migration of HUVEC, indicating that autophagy is definitely required for EFs-guided migration of cells. Mechanistically, we identified the intracellular reactive oxygen species (ROS) as a crucial mediator in EFs-triggered autophagy through augmenting the silencing information regulator 2 related enzyme1 (SIRT1)/forkhead box protein O1 (FOXO1) signaling. Either ROS scavenging or SIRT1 knockdown eliminated the EFs-triggered autophagy in HUVEC. Further study showed that SIRT1 promoted FOXO1 deacetylation, facilitating its nuclear accumulation and transcriptional activity, and thereby activating autophagy in EFs-treated HUVECs. In conclusion, our study demonstrated a pivotal role for autophagy in EFs-induced directed migration of HUVECs through the ROS/SIRT1/FOXO1 pathway, and provided a novel theoretical foundation for angiogenesis.