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

IM Fierro, JL Kutok, CN Serhan - Journal of Pharmacology and Experimental …, 2002 - ASPET
IM Fierro, JL Kutok, CN Serhan
Journal of Pharmacology and Experimental Therapeutics, 2002ASPET
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 15 R 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 …
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 A4(denoted ATL-1), which proved to be a potent inhibitor of angiogenesis. This ATL inhibited endothelial cell proliferation in the 1 to 10 nM range by ∼50% in cells stimulated with either vascular endothelial growth factor (VEGF) at 3 ng/ml or leukotriene D4 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 μg/mouse) reduced by ∼50% 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.
ASPET