Novel Lipid Mediator Regulators of Endothelial Cell Proliferation and Migration: Aspirin-Triggered-15R-Lipoxin A₄and Lipoxin A₄

Abstract

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 angiogenesis. This ATL inhibited endothelial cell proliferation in the 1 to 10 nM range by ϳ50% 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 g/mouse) reduced by ϳ50% 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.

Lipoxins: regulators of resolution

“…Ata cellular level LXA4 has been shown to modulate the proliferation of mesangial cells induced by cytokines and growth factors that have been implicated not only in GN but also in other disorders such as diabetic nephropathy and in the development of renal fibrosis. LXA4 has been shown to inhibit mesangial cell proliferation in response to LTD4 [12,13] and to counteract PDGF-induced fibrosis elated gene expression in mesangial cells and renal epithelia [39]suggesting that LXA4 might act as a potential anti-fibrotic agent preventing growth factor induced matrix production and the progression of renal disease. This is further enhanced by other experimental evidence that shows LXA4 modulates TNFα induced proliferation, cytokine release as well as CTGF mediated release of fractaline, MCP-1 and RANTES [40].…”

“…The partial antagonism of a subclass of peptide receptors (CysLTs) is a potential mechanism through which LXs may contribute to the anti-inflammatory actions of LX in several tissues other than leukocytes [8,9]. Further studies show that LX and ATL inhibit proliferation induced by growth factors such as PDGF [9], EGF [10], CTGF [11] and VEGF [12,13] with a mechanism that involves cross talk between ALX/FPR2 and receptor tyrosine kinases. Another potential receptor for LX is the ligand activated transcription factor aryl hydrocarbon receptor ( AhR), with both innate and acquired immune responses in dendritic cells being modulated through AhR and ALX/FPR2 activation [14].…”

Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation

“…These aspirin-triggered lipoxins (ATLs) (9) bear R configuration at carbon 15, which becomes epimeric to the original 15-lipoxygenase-initiated lipoxin biosynthesis pathway with carbon 15 of S configuration (10). The ATLs are more resistant to metabolic inactivation than lipoxins (11) and also possess antiinflammatory and pro-resolving actions in a wide range of inflammatory diseases, such as dermal inflammation (12), periodontitis (13), and inflammatory angiogenesis (14).…”

Increased dietary intake of ω-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis

“…The role of lipids in angiogenesis is just beginning to be defined 3,4 . The major polyunsaturated fatty acids (PUFA) found in the retina are docosahexaenoic acid (DHA; C22:6ω-3) and arachidonic acid (C20:4ω-6), both found primarily in neural and vascular cell membrane phospholipids 5 .…”