title: Nox2-derived reactive oxygen species contribute to hypercholesterolemia-induced inhibition of neovascularization: effects on endothelial progenitor cells and mature endothelial cells.
abstract: BACKGROUND
  Hypercholesterolemia has been associated with impaired angiogenesis and reduced blood flow recuperation after ischemia. However, the precise mechanisms involved are unknown. Here we investigated the role of Nox2-derived reactive oxygen species (ROS) in the modulation of neovascularization by hypercholesterolemia.
  
  
  RESULTS
  Mice deficient for the Nox2-containing NADPH oxidase (Nox2(-/-)) and control mice (Nox2(+/+)) were put on a high cholesterol diet (HCD) for a total of 15 weeks. After three months, hindlimb ischemia was surgically induced by femoral artery removal. Nox2 expression and oxidative stress levels in ischemic tissues were significantly increased by HCD in control mice, but not in Nox2(-/-) mice. Nox2(-/-) mice were also protected against hypercholesterolemia-induced impairment of neovascularization, as demonstrated by faster blood flow recovery after ischemia and increased capillary density in ischemic muscles. Nox2 deficiency was associated with preserved activity of eNOS in ischemic tissues, and improved activity of endothelial progenitor cells (EPCs). In vitro, HUVECs treated with the NADPH oxidase inhibitor apocynin or endothelial cells isolated from the aorta of Nox2(-/-) mice exhibited reduced ROS formation following exposure to oxLDL. This was associated with improved nitric oxide (NO) bioavailability and protection against oxLDL-induced inhibition of angiogenic activities.
  
  
  CONCLUSIONS
  Nox2-containing NADPH oxidase deficiency protects against hypercholesterolemia-induced impairment of neovascularization. The potential mechanisms involved include reduced ROS formation, preserved activation of angiogenic signals, and improved functional activities of EPCs and mature endothelial cells.
authors.affiliation: Department of Cardiovascular Research Centre, Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Paola
authors.initials: P
authors.lastname: Haddad
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dussault
authors.forename: Jessika
authors.initials: J
authors.lastname: Groleau
authors.forename: Julie
authors.initials: J
authors.lastname: Turgeon
authors.forename: Fritz
authors.initials: F
authors.lastname: Maingrette
authors.forename: Alain
authors.initials: A
authors.lastname: Rivard
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006614:Hindlimb; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006937:Hypercholesterolemia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D007511:Ischemia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020127:Recovery of Function; D012039:Regional Blood Flow; D013234:Stem Cells / Q000201:enzymology*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000098:Acetophenones; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; C099252:oxidized low density lipoprotein; D016222:Fibroblast Growth Factor 2; D009569:Nitric Oxide; C056165:acetovanillone; C056558:CYBB protein, human; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases