Lipoxin A4: anti-inflammatory and anti-angiogenic impact on endothelial cells

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 LXA(4) on endothelial cell inflammatory, proliferative, and antigenic responses. Using HUVECs we demonstrate that LXA(4) inhibits vascular endothelial growth factor (VEGF)-stimulated inflammatory responses including IL-6, TNF-alpha, IFN-gamma and IL-8 secretion, as well as endothelial ICAM-1 expression. Interestingly, LXA(4) up-regulated IL-10 production from HUVECs. Consistent with these antiinflammatory and proresolution responses to LXA(4), we demonstrate that LXA(4) inhibited leukotriene D(4) and VEGF-stimulated proliferation and angiogenesis as determined by tube formation of HUVECs. We have explored the underlying molecular mechanisms and demonstrate that LXA(4) 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-gamma, ERK1/2, and Akt.