Regulation of vegf-induced endothelial cell migration by mitochondrial reactive oxygen species

Youxue Wang, Qun S. Zang, Zijuan Liu, Qian Wu, David Maass, Genevieve Dulan, Philip W. Shaul, Lisa Melito, Doug E. Frantz, Jessica A. Kilgore, Noelle S. Williams, Lance S. Terada, Fiemu E. Nwariaku

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

Endothelial migration is a crucial aspect of a variety of physiologic and pathologic conditions including atherosclerosis and vascular repair. Reactive oxygen species (ROS) function as second messengers during endothelial migration. Multiple intracellular sources of ROS are regulated by cellular context, external stimulus, and the microenvironment. However, the predominant source of ROS during endothelial cell (EC) migration and the mechanisms by which ROS regulate cell migration are incompletely understood. In this study, we tested the hypothesis that mitochondriaderived ROS (mtROS) regulate EC migration. In cultured human umbilical vein endothelial cells, VEGF increased mitochondrial metabolism, promoted mtROS production, and induced cell migration. Either the targeted mitochondrial delivery of the antioxidant, vitamin E (Mito-Vit-E), or the depletion of mitochondrial DNA abrogated VEGF-mediated mtROS production. Overexpression of mitochondrial catalase also inhibited VEGF-induced mitochondrial metabolism, Rac activation, and cell migration. Furthermore, these interventions suppressed VEGF-stimulated EC migration and blocked Rac1 activation in endothelial cells. Constitutively active Rac1 reversed Mito-Vit-E-induced inhibition of EC migration. Mito-Vit-E also attenuated carotid artery reendothelialization in vivo. These results provide strong evidence that mtROS regulate EC migration through Rac-1.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume301
Issue number3
DOIs
StatePublished - Sep 2011

Fingerprint

Vascular Endothelial Growth Factor A
Cell Movement
Reactive Oxygen Species
Endothelial Cells
Human Umbilical Vein Endothelial Cells
Second Messenger Systems
Vitamin E
Mitochondrial DNA
Carotid Arteries
Catalase
Blood Vessels
Atherosclerosis
Antioxidants

Keywords

  • Antioxidants
  • Endothelial cells
  • Mitochondria
  • Oxidant signaling
  • Reactive oxygen species

ASJC Scopus subject areas

  • Cell Biology
  • Physiology

Cite this

Regulation of vegf-induced endothelial cell migration by mitochondrial reactive oxygen species. / Wang, Youxue; Zang, Qun S.; Liu, Zijuan; Wu, Qian; Maass, David; Dulan, Genevieve; Shaul, Philip W.; Melito, Lisa; Frantz, Doug E.; Kilgore, Jessica A.; Williams, Noelle S.; Terada, Lance S.; Nwariaku, Fiemu E.

In: American Journal of Physiology - Cell Physiology, Vol. 301, No. 3, 09.2011.

Research output: Contribution to journalArticle

Wang, Youxue ; Zang, Qun S. ; Liu, Zijuan ; Wu, Qian ; Maass, David ; Dulan, Genevieve ; Shaul, Philip W. ; Melito, Lisa ; Frantz, Doug E. ; Kilgore, Jessica A. ; Williams, Noelle S. ; Terada, Lance S. ; Nwariaku, Fiemu E. / Regulation of vegf-induced endothelial cell migration by mitochondrial reactive oxygen species. In: American Journal of Physiology - Cell Physiology. 2011 ; Vol. 301, No. 3.
@article{6ed3ac3b9f844a3fbe5559d859a23430,
title = "Regulation of vegf-induced endothelial cell migration by mitochondrial reactive oxygen species",
abstract = "Endothelial migration is a crucial aspect of a variety of physiologic and pathologic conditions including atherosclerosis and vascular repair. Reactive oxygen species (ROS) function as second messengers during endothelial migration. Multiple intracellular sources of ROS are regulated by cellular context, external stimulus, and the microenvironment. However, the predominant source of ROS during endothelial cell (EC) migration and the mechanisms by which ROS regulate cell migration are incompletely understood. In this study, we tested the hypothesis that mitochondriaderived ROS (mtROS) regulate EC migration. In cultured human umbilical vein endothelial cells, VEGF increased mitochondrial metabolism, promoted mtROS production, and induced cell migration. Either the targeted mitochondrial delivery of the antioxidant, vitamin E (Mito-Vit-E), or the depletion of mitochondrial DNA abrogated VEGF-mediated mtROS production. Overexpression of mitochondrial catalase also inhibited VEGF-induced mitochondrial metabolism, Rac activation, and cell migration. Furthermore, these interventions suppressed VEGF-stimulated EC migration and blocked Rac1 activation in endothelial cells. Constitutively active Rac1 reversed Mito-Vit-E-induced inhibition of EC migration. Mito-Vit-E also attenuated carotid artery reendothelialization in vivo. These results provide strong evidence that mtROS regulate EC migration through Rac-1.",
keywords = "Antioxidants, Endothelial cells, Mitochondria, Oxidant signaling, Reactive oxygen species",
author = "Youxue Wang and Zang, {Qun S.} and Zijuan Liu and Qian Wu and David Maass and Genevieve Dulan and Shaul, {Philip W.} and Lisa Melito and Frantz, {Doug E.} and Kilgore, {Jessica A.} and Williams, {Noelle S.} and Terada, {Lance S.} and Nwariaku, {Fiemu E.}",
year = "2011",
month = "9",
doi = "10.1152/ajpcell.00322.2010",
language = "English (US)",
volume = "301",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "3",

}

TY - JOUR

T1 - Regulation of vegf-induced endothelial cell migration by mitochondrial reactive oxygen species

AU - Wang, Youxue

AU - Zang, Qun S.

AU - Liu, Zijuan

AU - Wu, Qian

AU - Maass, David

AU - Dulan, Genevieve

AU - Shaul, Philip W.

AU - Melito, Lisa

AU - Frantz, Doug E.

AU - Kilgore, Jessica A.

AU - Williams, Noelle S.

AU - Terada, Lance S.

AU - Nwariaku, Fiemu E.

PY - 2011/9

Y1 - 2011/9

N2 - Endothelial migration is a crucial aspect of a variety of physiologic and pathologic conditions including atherosclerosis and vascular repair. Reactive oxygen species (ROS) function as second messengers during endothelial migration. Multiple intracellular sources of ROS are regulated by cellular context, external stimulus, and the microenvironment. However, the predominant source of ROS during endothelial cell (EC) migration and the mechanisms by which ROS regulate cell migration are incompletely understood. In this study, we tested the hypothesis that mitochondriaderived ROS (mtROS) regulate EC migration. In cultured human umbilical vein endothelial cells, VEGF increased mitochondrial metabolism, promoted mtROS production, and induced cell migration. Either the targeted mitochondrial delivery of the antioxidant, vitamin E (Mito-Vit-E), or the depletion of mitochondrial DNA abrogated VEGF-mediated mtROS production. Overexpression of mitochondrial catalase also inhibited VEGF-induced mitochondrial metabolism, Rac activation, and cell migration. Furthermore, these interventions suppressed VEGF-stimulated EC migration and blocked Rac1 activation in endothelial cells. Constitutively active Rac1 reversed Mito-Vit-E-induced inhibition of EC migration. Mito-Vit-E also attenuated carotid artery reendothelialization in vivo. These results provide strong evidence that mtROS regulate EC migration through Rac-1.

AB - Endothelial migration is a crucial aspect of a variety of physiologic and pathologic conditions including atherosclerosis and vascular repair. Reactive oxygen species (ROS) function as second messengers during endothelial migration. Multiple intracellular sources of ROS are regulated by cellular context, external stimulus, and the microenvironment. However, the predominant source of ROS during endothelial cell (EC) migration and the mechanisms by which ROS regulate cell migration are incompletely understood. In this study, we tested the hypothesis that mitochondriaderived ROS (mtROS) regulate EC migration. In cultured human umbilical vein endothelial cells, VEGF increased mitochondrial metabolism, promoted mtROS production, and induced cell migration. Either the targeted mitochondrial delivery of the antioxidant, vitamin E (Mito-Vit-E), or the depletion of mitochondrial DNA abrogated VEGF-mediated mtROS production. Overexpression of mitochondrial catalase also inhibited VEGF-induced mitochondrial metabolism, Rac activation, and cell migration. Furthermore, these interventions suppressed VEGF-stimulated EC migration and blocked Rac1 activation in endothelial cells. Constitutively active Rac1 reversed Mito-Vit-E-induced inhibition of EC migration. Mito-Vit-E also attenuated carotid artery reendothelialization in vivo. These results provide strong evidence that mtROS regulate EC migration through Rac-1.

KW - Antioxidants

KW - Endothelial cells

KW - Mitochondria

KW - Oxidant signaling

KW - Reactive oxygen species

UR - http://www.scopus.com/inward/record.url?scp=80052197530&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052197530&partnerID=8YFLogxK

U2 - 10.1152/ajpcell.00322.2010

DO - 10.1152/ajpcell.00322.2010

M3 - Article

VL - 301

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 3

ER -