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Extracellular SOD-Derived H2O2 Promotes VEGF Signaling in Caveolae/Lipid Rafts and Post-Ischemic Angiogenesis in Mice

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Title: Extracellular SOD-Derived H2O2 Promotes VEGF Signaling in Caveolae/Lipid Rafts and Post-Ischemic Angiogenesis in Mice
Author(s): Oshikawa, Jin; Urao, Norifumi; Kim, Ha Won; Kaplan, Nihal; Razvi, Masooma; McKinney, Ronald; Poole, Leslie B.; Fukai, Tohru; Ushio-Fukai, Masuko
Subject(s): VEGF signaling H2O2
Abstract: Reactive oxygen species (ROS), in particular, H2O2, is essential for full activation of VEGF receptor2 (VEGFR2) signaling involved in endothelial cell (EC) proliferation and migration. Extracellular superoxide dismutase (ecSOD) is a major secreted extracellular enzyme that catalyzes the dismutation of superoxide to H2O2, and anchors to EC surface through heparinbinding domain (HBD). Mice lacking ecSOD show impaired postnatal angiogenesis. However, it is unknown whether ecSODderived H2O2 regulates VEGF signaling. Here we show that gene transfer of ecSOD, but not ecSOD lacking HBD (ecSODDHBD), increases H2O2 levels in adductor muscle of mice, and promotes angiogenesis after hindlimb ischemia. Mice lacking ecSOD show reduction of H2O2 in non-ischemic and ischemic limbs. In vitro, overexpression of ecSOD, but not ecSOD-DHBD, in cultured medium in ECs enhances VEGF-induced tyrosine phosphorylation of VEGFR2 (VEGFR2-pY), which is prevented by short-term pretreatment with catalase that scavenges extracellular H2O2. Either exogenous H2O2 (,500 mM), which is diffusible, or nitric oxide donor has no effect on VEGF-induced VEGFR2-pY. These suggest that ecSOD binding to ECs via HBD is required for localized generation of extracellular H2O2 to regulate VEGFR2-pY. Mechanistically, VEGF-induced VEGFR2-pY in caveolae/lipid rafts, but non-lipid rafts, is enhanced by ecSOD, which localizes at lipid rafts via HBD. One of the targets of ROS is protein tyrosine phosphatases (PTPs). ecSOD induces oxidation and inactivation of both PTP1B and DEP1, which negatively regulates VEGFR2-pY, in caveolae/lipid rafts, but not non-lipid rafts. Disruption of caveolae/lipid rafts, or PTPs inhibitor orthovanadate, or siRNAs for PTP1B and DEP1 enhances VEGF-induced VEGFR2-pY, which prevents ecSODinduced effect. Functionally, ecSOD promotes VEGF-stimulated EC migration and proliferation. In summary, extracellular H2O2 generated by ecSOD localized at caveolae/lipid rafts via HBD promotes VEGFR2 signaling via oxidative inactivation of PTPs in these microdomains. Thus, ecSOD is a potential therapeutic target for angiogenesis-dependent cardiovascular diseases.
Issue Date: 2010-04-21
Publisher: Public Library of Science
Citation Info: Oshikawa, J., Urao, N., Kim, H. W., Kaplan, N., Razvi, M., McKinney, R., Poole, L. B., Fukai, T., & Ushio-Fukai, M. 2010. Extracellular SOD-derived H2O2 promotes VEGF signaling in caveolae/lipid rafts and post-ischemic angiogenesis in mice. PLoS One, 5(4): e10189. DOI: 10.1371/journal.pone.0010189
Type: Article
Description: © 2010 Oshikawa 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. The original version is available through the Public Library of Science at DOI: 10.1371/journal.pone.0010189.
URI: http://hdl.handle.net/10027/8266
ISSN: 1932-6203
Sponsor: This research was supported by National Institutes of Health (NIH) R01 Heart and Lung (HL)077524 and HL077524-S1 (to M.U.-F.), HL070187 (to T.F.) and Cancer (CA)126659 (to L.B.P.), American Heart Association (AHA) Grant-In-Aid 0755805Z (to M.U.-F.) and AHA National Center Research Program (NCRP) Innovative Research Grant 0970336N (to M.U.-F), AHA Post-doctoral Fellowship 09POST2250151 (to N.U.), Ruth L. Kirschstein-National Service Research Award (Kirschstein-NRSA) T32 Training Grant (to N.K. and M.R.), Uehara Memorial Foundation and Naito Foundation (to J.O.).
Date Available in INDIGO: 2012-04-15
 

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