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 mitochondria-derived 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.
authors.affiliation: Dept. of Surgery, The Univ. of Texas Southwestern Medical Cente at Dallas, 75390-9156, USA.
authors.forename: Youxue
authors.initials: Y
authors.lastname: Wang
authors.forename: Qun S
authors.initials: QS
authors.lastname: Zang
authors.forename: Zijuan
authors.initials: Z
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.forename: David
authors.initials: D
authors.lastname: Maass
authors.forename: Genevieve
authors.initials: G
authors.lastname: Dulan
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
authors.forename: Lisa
authors.initials: L
authors.lastname: Melito
authors.forename: Doug E
authors.initials: DE
authors.lastname: Frantz
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Kilgore
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.forename: Lance S
authors.initials: LS
authors.lastname: Terada
authors.forename: Fiemu E
authors.initials: FE
authors.lastname: Nwariaku
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000473:pathology; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000293:injuries / Q000473:pathology / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D014810:Vitamin E / Q000494:pharmacology; D054462:p21-Activated Kinases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: C107953:RAC1 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014841:von Willebrand Factor; D013481:Superoxides; D014810:Vitamin E; D006861:Hydrogen Peroxide; D002374:Catalase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D003576:Electron Transport Complex IV; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D020830:rac1 GTP-Binding Protein