title: NADPH oxidase Nox2 is required for hypoxia-induced mobilization of endothelial progenitor cells.
abstract: BACKGROUND
  Endothelial progenitor cells (EPCs, defined as sca-1(+)flk-1(+)lin(-) mononuclear blood cells) contribute to vascular repair. The role of hypoxia and reactive oxygen species (ROS) in mobilization and function of these cells is incompletely understood.
  
  
  OBJECTIVE
  We studied the contribution of the NADPH oxidase Nox2, an important vascular source of ROS in this context.
  
  
  RESULTS
  Hypoxia (10% oxygen) induced the mobilization of EPCs in wild-type (WT) and Nox1 but not in Nox2 knockout (Nox2(y/-)) mice. As erythropoietin (EPO) is known to induce EPC mobilization, we focused on this hormone. EPO induced the mobilization of EPCs in WT and Nox1(y/-) but not Nox2(y/-) animals. Transplantation of bone marrow from Nox2(y/-) mice into WT-mice blocked mobilization in response to hypoxia and EPO, whereas transplantation of WT bone marrow into Nox2(y/-) mice restored mobilization. Reendothelialization of the injured mouse carotid artery was enhanced by hypoxia as well as by EPO, and this effect was not observed in Nox2(y/-) mice or after transplantation of Nox2(y/-) bone marrow. In cultured EPCs from WT but not Nox2(y/-) mice, EPO induced ROS production, migration, and proliferation. EPO signaling involves the STAT5 transcription factor. EPO-induced STAT5-dependent reporter gene expression was absent in Nox2-deficient cells. siRNA against the redox-sensitive phosphatase SHP-2 restored EPO-mediated STAT5 induction and inhibition of SHP-2 restored EPO-induced migration in Nox2-deficient cells
  
  
  CONCLUSIONS
  We conclude that Nox2-derived ROS inactivate SHP-2 and thereby facilitate EPO signaling in EPCs to promote hypoxia-induced mobilization and vascular repair by these cells.
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schröder
authors.forename: Andreas
authors.initials: A
authors.lastname: Kohnen
authors.forename: Alexandra
authors.initials: A
authors.lastname: Aicher
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Liehn
authors.forename: Tom
authors.initials: T
authors.lastname: Büchse
authors.forename: Stefan
authors.initials: S
authors.lastname: Stein
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
mesh_terms: D000818:Animals; D000950:Antigens, Ly; D016026:Bone Marrow Transplantation; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology; D020212:Carotid Artery Injuries / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D004921:Erythropoietin / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D000860:Hypoxia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000201:enzymology* / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2; D014945:Wound Healing / Q000235:genetics
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D050799:STAT5 Transcription Factor; D004921:Erythropoietin; D009247:NADH, NADPH Oxidoreductases; C488842:Cybb protein, mouse; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11