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Molecular and Cellular Biology, May 2009, p. 2469-2480, Vol. 29, No. 9
0270-7306/09/$08.00+0 doi:10.1128/MCB.01304-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
A Role for a CXCR2/Phosphatidylinositol 3-Kinase 
Signaling Axis in Acute and Chronic Vascular Permeability
,
Julie Gavard,1,4,5*
Xu Hou,2
Yi Qu,2
Andrius Masedunskas,1,3
Daniel Martin,1
Roberto Weigert,1,3
Xuri Li,2 and
J. Silvio Gutkind1*
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Rm. 211, Bethesda, Maryland 20892,1 Unit of Vascular Retinal Neurobiology Research, Porter Neuroscience Research Center, National Eye Institute, National Institutes of Health, 35 Lincoln Drive, Rm. 2A-108, MSC 3731, Bethesda, Maryland 20892,2 Intracellular Membrane Trafficking Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Rm. 303A, Bethesda, Maryland 20892,3 Institut Cochin, Universite Paris Descartes, CNRS (UMR 8104), Paris, France,4 INSERM, U567, Paris, France5
Received 16 August 2008/ Returned for modification 20 October 2008/ Accepted 2 February 2009
Most proangiogenic polypeptide growth factors and chemokines enhance vascular permeability, including vascular endothelial growth factor (VEGF), the main target for anti-angiogenic-based therapies, and interleukin-8 (IL-8), a potent proinflammatory mediator. Here, we show that in endothelial cells IL-8 initiates a signaling route that converges with that deployed by VEGF at the level of the small GTPase Rac1 and that both act through the p21-activated kinase to promote the phosphorylation and internalization of VE-cadherin. However, whereas VEGF activates Rac1 through Src-related kinases, IL-8 specifically signals to Rac1 through its cognate G protein-linked receptor, CXCR2, and the stimulation of the phosphatidylinositol 3-kinase 
(PI3K) catalytic isoform, thereby providing a specific molecular targeted intervention in vascular permeability. These results prompted us to investigate the potential role of IL-8 signaling in a mouse model for retinal vascular hyperpermeability. Importantly, we observed that IL-8 is upregulated upon laser-induced retinal damage, which recapitulates enhanced vascularization, leakage, and inflammatory responses. Moreover, blockade of CXCR2 and PI3K was able to limit neovascularization and choroidal edema, as well as macrophage infiltration, therefore contributing to reduce retinal damage. These findings indicate that the CXCR2 and PI3K signaling pathway may represent a suitable target for the development of novel therapeutic strategies for human diseases characterized by vascular leakage.
* Corresponding author. Mailing address for J. Silvio Gutkind: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Rm. 211, Bethesda, MD 20892. Phone: (301) 496-6259. Fax: (301) 402-0821. E-mail: sg39v{at}nih.gov. Mailing address for Julie Gavard: Institut Cochin, CNRS (UMR8104), INSERM, U567, Université Paris Descartes, 22 rue Mechain, 75014 Paris, France. Phone: 33-140-516-24. Fax: 33-140-516-30. E-mail: julie.gavard{at}inserm.fr
Published ahead of print on 2 March 2009.
Supplemental material for this article may be found at http://mcb.asm.org/.
Molecular and Cellular Biology, May 2009, p. 2469-2480, Vol. 29, No. 9
0270-7306/09/$08.00+0 doi:10.1128/MCB.01304-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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