title: Reactive oxygen species regulate osteopontin expression in a murine model of postischemic neovascularization.
abstract: OBJECTIVE
  Previous findings from our laboratory demonstrated that neovascularization was impaired in osteopontin (OPN) knockout animals. However, the mechanisms responsible for the regulation of OPN expression in the setting of ischemia remain undefined. Therefore, we sought to determine whether OPN is upregulated in response to ischemia and hypothesized that hydrogen peroxide (H(2)O(2)) is a critical component of the signaling mechanism by which OPN expression is upregulated in response to ischemia in vivo.
  
  
  RESULTS
  To determine whether ischemic injury upregulates OPN, we used a murine model of hindlimb ischemia. Femoral artery ligation in C57BL/6 mice significantly increased OPN expression and H(2)O(2) production. Infusion of C57BL/6 mice with polyethylene glycol-catalase (10 000 U/kg per day) or the use of transgenic mice with smooth muscle cell-specific catalase overexpression blunted ischemia-induced OPN, suggesting ischemia-induced OPN expression is H(2)O(2)-dependent. Decreased H(2)O(2)-mediated OPN blunted reperfusion and collateral formation in vivo. In contrast, the overexpression of OPN using lentivirus restored neovascularization.
  
  
  CONCLUSIONS
  Scavenging H(2)O(2) blocks ischemia-induced OPN expression, providing evidence that ischemia-induced OPN expression is H(2)O(2) dependent. Decreased OPN expression impaired neovascularization, whereas overexpression of OPN increased angiogenesis, supporting our hypothesis that OPN is a critical mediator of postischemic neovascularization and a potential novel therapeutic target for inducing new vessel growth.
authors.affiliation: Division of Cardiology, Emory University School of Medicine, 1639 Pierce Drive, Suite 319 WMB, Atlanta, GA 30322, USA.
authors.forename: Alicia N
authors.initials: AN
authors.lastname: Lyle
authors.forename: Giji
authors.initials: G
authors.lastname: Joseph
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Fan
authors.forename: Daiana
authors.initials: D
authors.lastname: Weiss
authors.forename: Natalia
authors.initials: N
authors.lastname: Landázuri
authors.forename: W Robert
authors.initials: WR
authors.lastname: Taylor
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D002374:Catalase / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003097:Collateral Circulation; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006614:Hindlimb; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007262:Infusions, Intravenous; D007511:Ischemia / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000098:blood supply*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011092:Polyethylene Glycols / Q000008:administration & dosage; D012039:Regional Blood Flow; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation; D055114:X-Ray Microtomography
chemical_list: D000975:Antioxidants; C506895:SPP1 protein, human; C506896:Spp1 protein, mouse; C070295:catalase-polyethylene glycol; D053495:Osteopontin; D011092:Polyethylene Glycols; D006861:Hydrogen Peroxide; D002374:Catalase