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

109 Scopus citations

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)
Pages (from-to)C695-C704
JournalAmerican Journal of Physiology - Cell Physiology
Volume301
Issue number3
DOIs
StatePublished - Sep 2011

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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