Targeting Vascular NADPH Oxidase 1 Blocks Tumor Angiogenesis through a PPARa Mediated Mechanism

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 PPARa, a regulator of NF-kB. Administration of a novel NOX-specific inhibitor reduced angiogenesis and tumor growth in vivo in a PPARa dependent manner. In conclusion, vascular NOX1 is a critical mediator of angiogenesis and an attractive target for anti-angiogenic therapies. Citation: Garrido-Urbani S, Jemelin S, Deffert C, Carnesecchi S, Basset O, et al. (2011) Targeting Vascular NADPH Oxidase 1 Blocks Tumor Angiogenesis through a PPARa Mediated Mechanism. PLoS ONE 6(2): e14665. doi:10.1371/journal.pone.0014665 Editor: Stefan Wölfl, Universität Heidelberg, Germany Received June 16, 2010; Accepted January 11, 2011; Published February 7, 2011 Copyright: 2011 Garrido-Urbani et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Swiss Cancer League, KPS-OCS 01812-12-2005 and by the Swiss National Science Foundation, FNS-310030-120184. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This study was also funded by GenKyoTex S.A. as employer of some of the authors. This funder was implicated in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: A patent is pending on GKT136901 with PP as inventor and GenKyoTex as owner of the patent. PP, CS and K-HK own shares of GenKyoTex. A patent is pending on fulvene-5, with JLA as inventor and Emory University as owner of the patent. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: [email protected]