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

Abstract

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-α, IFN-γ 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-γ, ERK1/2, and Akt.