Endogenous LXA4 circuits are determinants of pathological angiogenesis in response to chronic injury.
Inflammation and angiogenesis are intimately linked, and their dysregulation leads to pathological angiogenesis in human diseases. 15-lipoxygenase (15-LOX) and lipoxin A(4) receptors (ALX) constitute a LXA(4) circuit that is a key feature of inflammatory resolution. LXA(4) analogs have been shown to regulate vascular endothelial growth factor (VEGF)-A-induced angiogenic response in vitro. 15-LOX and ALX are highly expressed in the avascular and immune-privileged cornea. However, the role of this endogenous LXA(4) circuit in pathological neovascularization has not been determined. We report that suture-induced chronic injury in the cornea triggered polymorphonuclear leukocytes (PMN) infiltration, pathological neovascularization, and up-regulation of mediators of inflammatory angiogenesis, namely VEGF-A and the VEGF-3 receptor (FLT4). Up-regulation of the VEGF circuit and neovascularization correlated with selective changes in both 15-LOX (Alox15) and ALX (Fpr-rs2) expression and a temporally defined increase in basal 15-LOX activity. More importantly, genetic deletion of 15-LOX or 5-LOX, key and obligatory enzymes in the formation of LXA(4), respectively, led to exacerbated inflammatory neovascularization coincident with increased VEGF-A and FLT4 expression. Direct topical treatment with LXA(4), but not its metabolic precursor 15-hydroxyeicosatetraenoic acid, reduced expression of VEGF-A and FLT4 and inflammatory angiogenesis and rescued 15-LOX knockout mice from exacerbated angiogenesis. In summary, our findings and the prominent expression of 15-LOX and ALX in epithelial cells and macrophages place the LXA(4) circuit as an endogenous regulator of pathological angiogenesis.
Leedom
Alexander J
AJ
Vision Science Program, School of Optometry, University of California, Berkeley, CA 94720-2020, USA.
Sullivan
Aaron B
AB
Dong
Baiyan
B
Lau
Denise
D
Gronert
Karsten
K
D000287:Administration, Topical; D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D012898:Autacoids / Q000378:metabolism; D003315:Cornea / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D003316:Corneal Diseases / Q000150:complications / Q000201:enzymology / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D017353:Gene Deletion; D007249:Inflammation / Q000150:complications / Q000201:enzymology; D044045:Lipoxins / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D009389:Neovascularization, Pathologic / Q000150:complications / Q000201:enzymology / Q000378:metabolism*; D010641:Phenotype
D012898:Autacoids; D044045:Lipoxins; C040527:lipoxin A4; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase