Hypoxia-dependent mitochondrial fission regulates endothelial progenitor cell migration, invasion, and tube formation.
Hypoxia-dependent mitochondrial fission regulates endothelial progenitor cell migration, invasion, and tube formation.
复制标题
DOI：
10.4196/kjpp.2018.22.2.203
复制
发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Kwon SM
中科院分区：
文献类型：
--
作者：
Kim DY;Jung SY;Kim YJ;Kang S;Park JH;Ji ST;Jang WB;Lamichane S;Lamichane BD;Chae YC;Lee D;Chung JS;Kwon SM
肿瘤失控、过度增殖导致缺氧微环境。为了满足他们对营养和氧气的需求，肿瘤血管生成是必需的。内皮祖细胞因其具有向内皮细胞分化的潜能而被认为是血管生成的主要来源。因此，了解缺氧条件下内皮祖细胞介导的血管生成机制对肿瘤治疗的发展至关重要。近年来，线粒体动力学已成为低氧条件下细胞功能和分化的关键机制。然而，线粒体动力学在低氧诱导的血管生成中的作用仍有待阐明。在这项研究中，我们证明了缺氧诱导的线粒体分裂加速了内皮祖细胞的生物活性。我们首先研究了低氧对EPC介导的血管生成的影响。在低氧条件下，细胞迁移、侵袭和管状形成显著增加；EPC表面标志物的表达没有变化。低氧以时间依赖方式诱导线粒体分裂。我们发现，低氧诱导的线粒体分裂是由动力蛋白相关蛋白Drp1触发的，具体地说，线粒体分裂的抑制标志Ser637处的磷酸化Drp1以低氧时间依赖的方式受损。为了确认Drp1在EPC介导的血管生成中的作用，我们使用选择性的Drp1抑制剂Mdivi-1和Drp1 siRNA分析了细胞的生物活性。DRp1沉默或Mdivi-1处理显著减少EPC的细胞迁移、侵袭和管状形成，但EPC表面标志物的表达没有变化。总之，我们发现了线粒体分裂在低氧诱导的血管生成中的一个新的作用。因此，我们认为特异性调控DRP1介导的线粒体动力学可能是EPC介导的肿瘤血管生成的一种潜在的治疗策略。
Tumor undergo uncontrolled, excessive proliferation leads to hypoxic microenvironment. To fulfill their demand for nutrient, and oxygen, tumor angiogenesis is required. Endothelial progenitor cells (EPCs) have been known to the main source of angiogenesis because of their potential to differentiation into endothelial cells. Therefore, understanding the mechanism of EPC-mediated angiogenesis in hypoxia is critical for development of cancer therapy. Recently, mitochondrial dynamics has emerged as a critical mechanism for cellular function and differentiation under hypoxic conditions. However, the role of mitochondrial dynamics in hypoxia-induced angiogenesis remains to be elucidated. In this study, we demonstrated that hypoxia-induced mitochondrial fission accelerates EPCs bioactivities. We first investigated the effect of hypoxia on EPC-mediated angiogenesis. Cell migration, invasion, and tube formation was significantly increased under hypoxic conditions; expression of EPC surface markers was unchanged. And mitochondrial fission was induced by hypoxia time-dependent manner. We found that hypoxia-induced mitochondrial fission was triggered by dynamin-related protein Drp1, specifically, phosphorylated DRP1 at Ser637, a suppression marker for mitochondrial fission, was impaired in hypoxia time-dependent manner. To confirm the role of DRP1 in EPC-mediated angiogenesis, we analyzed cell bioactivities using Mdivi-1, a selective DRP1 inhibitor, and DRP1 siRNA. DRP1 silencing or Mdivi-1 treatment dramatically reduced cell migration, invasion, and tube formation in EPCs, but the expression of EPC surface markers was unchanged. In conclusion, we uncovered a novel role of mitochondrial fission in hypoxia-induced angiogenesis. Therefore, we suggest that specific modulation of DRP1-mediated mitochondrial dynamics may be a potential therapeutic strategy in EPC-mediated tumor angiogenesis.
登录
查看更多内容
影响因子：
56.9
作者：
Asahara, T;Murohara, T;Isner, JM
通讯作者：
Isner, JM
影响因子：
11.1
作者：
Gao, Arwen W.;Canto, Carles;Houtkooper, Riekelt H.
通讯作者：
Houtkooper, Riekelt H.
影响因子：
4.5
作者：
Hager, Gudrun;Holnthoner, Wolfgang;Gabriel, Christian
通讯作者：
Gabriel, Christian
DOI：
10.1016/j.bbrc.2014.11.010
发表时间：
2015-01-02
影响因子：
3.1
作者：
Wang, Jingnan;Hansen, Karyn;Edwards, Robert;Van Houten, Bennett;Qian, Wei
通讯作者：
Qian, Wei
影响因子：
3.3
作者：
Sanderson TH;Raghunayakula S;Kumar R
通讯作者：
Kumar R