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Original Article

Korean J Physiol Pharmacol 2018; 22(2): 203-213

Published online March 1, 2018 https://doi.org/10.4196/kjpp.2018.22.2.203

Copyright © Korean J Physiol Pharmacol.

Hypoxia-dependent mitochondrial fission regulates endothelial progenitor cell migration, invasion, and tube formation

Da Yeon Kim1, Seok Yun Jung1, Yeon Ju Kim1, Songhwa Kang1, Ji Hye Park1, Seung Taek Ji1, Woong Bi Jang1, Shreekrishna Lamichane1, Babita Dahal Lamichane1, Young Chan Chae2, Dongjun Lee3, Joo Seop Chung4,*, and Sang-Mo Kwon1,*

1Department 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, 2School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, 3Department of Medical Science, Pusan National University School of Medicine, Yangsan 50612, 4Division of Hemato-Oncology, Department of Internal Medicine, Pusan National University Hospital Medical Research Institute, Busan 49241, Korea

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.

Keywords: Angiogenesis, DRP1, Endothelial progenitor cells, Hypoxia, Mitochondrial dynamics