title: Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARα mediated mechanism.
abstract: Reactive oxygen species, ROS, are regulators of endothelial cell migration, proliferation and survival, events critically involved in angiogenesis. Different isoforms of ROS-generating NOX enzymes are expressed in the vasculature and provide distinct signaling cues through differential localization and activation. We show that mice deficient in NOX1, but not NOX2 or NOX4, have impaired angiogenesis. NOX1 expression and activity is increased in primary mouse and human endothelial cells upon angiogenic stimulation. NOX1 silencing decreases endothelial cell migration and tube-like structure formation, through the inhibition of PPARα, a regulator of NF-κB. Administration of a novel NOX-specific inhibitor reduced angiogenesis and tumor growth in vivo in a PPARα dependent manner. In conclusion, vascular NOX1 is a critical mediator of angiogenesis and an attractive target for anti-angiogenic therapies.
authors.affiliation: Department of Pathology and Immunology, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Garrido-Urbani
authors.forename: Stephane
authors.initials: S
authors.lastname: Jemelin
authors.forename: Christine
authors.initials: C
authors.lastname: Deffert
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Carnesecchi
authors.forename: Olivier
authors.initials: O
authors.lastname: Basset
authors.forename: Cédric
authors.initials: C
authors.lastname: Szyndralewiez
authors.forename: Freddy
authors.initials: F
authors.lastname: Heitz
authors.forename: Patrick
authors.initials: P
authors.lastname: Page
authors.forename: Xavier
authors.initials: X
authors.lastname: Montet
authors.forename: Liliane
authors.initials: L
authors.lastname: Michalik
authors.forename: Jack
authors.initials: J
authors.lastname: Arbiser
authors.forename: Curzio
authors.initials: C
authors.lastname: Rüegg
authors.forename: Karl Heinz
authors.initials: KH
authors.lastname: Krause
authors.forename: Beat A
authors.initials: BA
authors.lastname: Imhof
authors.forename: Beat
authors.initials: B
authors.lastname: Imhof
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D018390:Gene Targeting; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D000074624:NADPH Oxidase 1; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics*; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C554850:2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo(4,3-c)pyridine-3,6(2H,5H)-dione; D020533:Angiogenesis Inhibitors; D047493:PPAR alpha; D011720:Pyrazoles; D011728:Pyridones; D034741:RNA, Small Interfering; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse