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Vol. 18, Issue 12, 5014-5023, December 2007

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Transactivation of Vascular Endothelial Growth Factor Receptor-2 by Interleukin-8 (IL-8/CXCL8) Is Required for IL-8/CXCL8-induced Endothelial Permeability

Melissa L. Petreaca^*,, Min Yao, Yan Liu, Kathryn DeFea^*,, and Manuela Martins-Green^*,

*Graduate Program in Cell, Molecular, and Developmental Biology, Department of Cell Biology and Neuroscience, and Division of Biomedical Sciences, University of California, Riverside, Riverside, CA 92521

Submitted January 5, 2007; Revised September 28, 2007; Accepted October 2, 2007
Monitoring Editor: Mark Ginsberg

Interleukin-8 (IL-8/CXCL8) is a chemokine that increases endothelial permeability during early stages of angiogenesis. However, the mechanisms involved in IL-8/CXCL8-induced permeability are poorly understood. Here, we show that permeability induced by this chemokine requires the activation of vascular endothelial growth factor receptor-2 (VEGFR2/fetal liver kinase 1/KDR). IL-8/CXCL8 stimulates VEGFR2 phosphorylation in a VEGF-independent manner, suggesting VEGFR2 transactivation. We investigated the possible contribution of physical interactions between VEGFR2 and the IL-8/CXCL8 receptors leading to VEGFR2 transactivation. Both IL-8 receptors interact with VEGFR2 after IL-8/CXCL8 treatment, and the time course of complex formation is comparable with that of VEGFR2 phosphorylation. Src kinases are involved upstream of receptor complex formation and VEGFR2 transactivation during IL-8/CXCL8-induced permeability. An inhibitor of Src kinases blocked IL-8/CXCL8-induced VEGFR2 phosphorylation, receptor complex formation, and endothelial permeability. Furthermore, inhibition of the VEGFR abolishes RhoA activation by IL-8/CXCL8, and gap formation, suggesting a mechanism whereby VEGFR2 transactivation mediates IL-8/CXCL8-induced permeability. This study points to VEGFR2 transactivation as an important signaling pathway used by chemokines such as IL-8/CXCL8, and it may lead to the development of new therapies that can be used in conditions involving increases in endothelial permeability or angiogenesis, particularly in pathological situations associated with both IL-8/CXCL8 and VEGF.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Manuela Martins-Green (manuela.martins{at}ucr.edu).

Abbreviations used: FITC, fluorescein isothiocyanate; Flk-1, fetal liver kinase 1; HMEC, human microvascular endothelial cell; hMVEC, primary human microvascular endothelial cell; IL-8, interleukin 8; PECAM-1, platelet endothelial cell adhesion molecule 1; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2.

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