Novel lipid mediator regulators of endothelial cell proliferation and migration: aspirin-triggered-15R-lipoxin A(4) and lipoxin A(4).
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 approximately 50% 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 microg/mouse) reduced by approximately 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.
Fierro
Iolanda M
IM
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. iolanda@uerj.br
Kutok
Jeffery L
JL
Serhan
Charles N
CN
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D015777:Eicosanoids / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D017572:Leukotriene A4 / Q000037:antagonists & inhibitors; D050356:Lipid Metabolism; D044045:Lipoxins; D008222:Lymphokines / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000473:pathology; D014470:Umbilical Cord / Q000166:cytology / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C447621:16-(4-fluorophenoxy)lipoxin A4; D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D016228:Endothelial Growth Factors; D006893:Hydroxyeicosatetraenoic Acids; D017572:Leukotriene A4; D044045:Lipoxins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C040527:lipoxin A4