Novel lipid mediator regulators of endothelial cell proliferation and migration:: Aspirin-triggered-15R-lipoxin A4 and lipoxin A4

Proliferative states such as chronic inflammation, ischemic diseases, and cancer are often accompanied by intense angiogenesis, a highly orchestrated process involving vessel sprouting, endothelial cell migration, proliferation, and maturation. Aspirin-triggered lipoxins (ATLs), the 15R enantiomeric counterparts of lipoxins (LXs), are endogenous mediators generated during multicellular responses that display potent immunomodulatory actions. Herein, we report a novel action for the ATL stable analog 15-epi-16-(para-fluoro)-phenoxy-lipoxin A(4) (denoted ATL-1), which proved to be a potent inhibitor of angio-genesis. This ATL inhibited endothelial cell proliferation in the 1 to 10 nM range by similar to50% in cells stimulated with either vascular endothelial growth factor (VEGF) at 3 ng/ml or leukotriene D-4 at 10 nM. In addition, ATL-1 (in a 10-100 nM range) inhibited VEGF (3 ng/ml)-induced endothelial cell chemotaxis. In a granuloma in vivo model of inflammatory angiogenesis, ATL-1 treatment (10 mug/mouse) reduced by similar to50% the angiogenic phenotype, as assessed by both vascular casting and fluorescence. Together, these results identify a novel and potent previously unappreciated action of aspirin-triggered 15-epi-LX.