Kim Da Yeon, Jung Seok Yun, Kim Yeon Ju, Kang Songhwa, Park Ji Hye, Ji Seung Taek, Jang Woong Bi, Lamichane Shreekrishna, Lamichane Babita Dahal, Chae Young Chan, Lee Dongjun, Chung Joo Seop, Kwon Sang-Mo
Department of Physiology, Laboratory for Vascular Medicine and Stem Cell Biology, Convergence Stem Cell Research Center, Medical Research Institute, Pusan National University School of Medicine, Yangsan 50612, Korea.
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Korea.
Korean J Physiol Pharmacol. 2018 Mar;22(2):203-213. doi: 10.4196/kjpp.2018.22.2.203. Epub 2018 Feb 23.
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.
肿瘤发生不受控制的过度增殖会导致缺氧微环境。为了满足对营养物质和氧气的需求，肿瘤需要血管生成。内皮祖细胞（EPCs）因其具有分化为内皮细胞的潜力，一直被认为是血管生成的主要来源。因此，了解缺氧条件下EPCs介导的血管生成机制对于癌症治疗的发展至关重要。最近，线粒体动力学已成为缺氧条件下细胞功能和分化的关键机制。然而，线粒体动力学在缺氧诱导的血管生成中的作用仍有待阐明。在本研究中，我们证明缺氧诱导的线粒体分裂加速了EPCs的生物活性。我们首先研究了缺氧对EPCs介导的血管生成的影响。在缺氧条件下，细胞迁移、侵袭和管腔形成显著增加；EPCs表面标志物的表达未发生变化。并且缺氧以时间依赖性方式诱导线粒体分裂。我们发现缺氧诱导的线粒体分裂是由动力相关蛋白Drp1触发的，具体而言，线粒体分裂的抑制标志物Ser637位点磷酸化的DRP1在缺氧条件下以时间依赖性方式受损。为了证实Drp1在EPCs介导的血管生成中的作用，我们使用选择性Drp1抑制剂Mdivi-1和Drp1 siRNA分析了细胞生物活性。Drp1沉默或Mdivi-1处理显著降低了EPCs的细胞迁移、侵袭和管腔形成，但EPCs表面标志物的表达未发生变化。总之，我们揭示了线粒体分裂在缺氧诱导的血管生成中的新作用。因此，我们认为特异性调节Drp1介导的线粒体动力学可能是EPCs介导的肿瘤血管生成的一种潜在治疗策略。
