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

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.

Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission–associated myocardial senescence

“…2B), suggesting that only FLNa directly associates with Drp1. Dephosphorylation of Drp1 at Ser 637 participates in mitochondrial fission, and hypoxic stress induces dephosphorylation of Drp1 Ser 637 in on July 4, 2020 http://stke.sciencemag.org/ Downloaded from endothelial progenitor cells (40). We investigated whether the phosphorylation state at Ser 637 on Drp1 alters the interaction with FLNa.…”

Dysfunctional cerebrovascular tone contributes to cognitive impairment in a non-obese rat model of prediabetic challenge: Role of suppression of autophagy and modulation by anti-diabetic drugs

“…Specifically, recent studies reported that hypoxia-induced mitochondrial fission via increased HIF-1α expression leading to increased DRP1 activity (57)(58)(59). This was indeed the case in the hippocampus of MHC-fed rats where increased DRP1 phosphorylation at Ser616 was observed.…”

OGR1 mediates the inhibitory effects of acidic environment on proliferation and angiogenesis of endothelial progenitor cells

“…Different microenvironments can have different effects on the proliferation and angiogenesis of EPCs. Kim et al (2018) found that a hypoxic microenvironment can promote proliferation, migration, and angiogenesis of human EPCs through mitochondrial division and related signaling pathways. However, Wu et al (2018) found that proliferation, migration, and angiogenesis of rat bone marrow-derived EPCs were inhibited in a high glucose micro-environment with hypoxia.…”