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Lipoxin A₄: Anti-Inflammatory and Anti-Angiogenic Impact on Endothelial Cells¹

School of Medicine and Medical Science, University College Dublin (UCD) Diabetes Research Centre, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland

Lipoxins (LX) are a class of eicosanoid that possesses a wide spectrum of antiinflammatory and proresolution bioactions. Here we have investigated the impact of the endogenously produced eicosanoid LXA₄ on endothelial cell inflammatory, proliferative, and antigenic responses. Using HUVECs we demonstrate that LXA₄ inhibits vascular endothelial growth factor (VEGF)-stimulated inflammatory responses including IL-6, TNF-, IFN- and IL-8 secretion, as well as endothelial ICAM-1 expression. Interestingly, LXA₄ up-regulated IL-10 production from HUVECs. Consistent with these antiinflammatory and proresolution responses to LXA₄, we demonstrate that LXA₄ inhibited leukotriene D₄ and VEGF-stimulated proliferation and angiogenesis as determined by tube formation of HUVECs. We have explored the underlying molecular mechanisms and demonstrate that LXA₄ pretreatment is associated with the decrease of VEGF-stimulated VEGF receptor 2 (KDR/FLK-1) phosphorylation and downstream signaling events including activation of phospholipase C-, ERK1/2, and Akt.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the European Commission FP6 Grant LSHM-CT-2004-005033, The Health Research Board and Science Foundation Ireland.

² Current address: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.

³ Address correspondence and reprint requests to Dr. Catherine Godson, School of Medicine and Medical Sciences, UCD Diabetes Research Centre, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

⁴ Abbreviations used in this paper: LX, lipoxins; ATL, aspirin-triggered LX; LTD₄, leukotriene D₄; VEGF, vascular endothelial growth factor; PLC, phospholipase C-; PDGF, platelet-derived growth factor; EGF, epidermal growth factor; L-NAME, N^G-nitro-L-arginine methyl ester.

⁵ The online version of this article contains supplemental material.