Hypoxia-dependent mitochondrial fission regulates endothelial progenitor cell migration, invasion, and tube formation.
10.4196/kjpp.2018.22.2.203
- Author:
Da Yeon KIM
1
;
Seok Yun JUNG
;
Yeon Ju KIM
;
Songhwa KANG
;
Ji Hye PARK
;
Seung Taek JI
;
Woong Bi JANG
;
Shreekrishna LAMICHANE
;
Babita Dahal LAMICHANE
;
Young Chan CHAE
;
Dongjun LEE
;
Joo Seop CHUNG
;
Sang Mo KWON
Author Information
1. 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. smkwon323@pusan.ac.kr
- Publication Type:Original Article
- Keywords:
Angiogenesis;
DRP1;
Endothelial progenitor cells;
Hypoxia;
Mitochondrial dynamics
- MeSH:
Anoxia;
Cell Movement;
Endothelial Cells;
Endothelial Progenitor Cells*;
Mitochondrial Dynamics*;
Oxygen;
RNA, Small Interfering
- From:The Korean Journal of Physiology and Pharmacology
2018;22(2):203-213
- CountryRepublic of Korea
- Language:English
-
Abstract:
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.
