title: Pathogenic role of the Wnt signaling pathway activation in laser-induced choroidal neovascularization.
abstract: OBJECTIVE
  Choroidal neovascularization (CNV) is a severe complication of AMD. The Wnt signaling pathway has been shown to mediate angiogenesis. The purpose of this study was to investigate the pathogenic role of the Wnt pathway in CNV and explore the therapeutic potential of a novel Wnt signaling inhibitor in CNV.
  
  
  METHODS
  Adult rats and mice were photocoagulated using diode laser to induce CNV. On the same day, the animals were intravitreally injected with a monoclonal antibody (Mab2F1) blocking LRP6 or nonspecific mouse IgG. The Wnt signaling activation and target gene expression in the eyecup were determined by Western blot analysis. Fundus angiography was used to examine leakage from the laser lesion. CNV areas were measured on choroidal flatmount using FITC-dextran.
  
  
  RESULTS
  Levels of Wnt pathway components and Wnt target gene expression were elevated in both laser-induced CNV rat and mouse eyecups, suggesting activation of the Wnt pathway. Significant suppression of Wnt signaling was observed in the Mab2F1 treatment group. Mab2F1 decreased vascular leakage from CNV lesions and reduced the neovascular area in laser-induced CNV rats. Mab2F1 inhibited the hypoxia-induced activation of Wnt signaling in cultured RPE cells. Mab2F1 also ameliorated retinal inflammation and vascular leakage in the eyecups of very low-density lipoprotein receptor knockout mice, a model of subretinal neovascularization.
  
  
  CONCLUSIONS
  The Wnt pathway is activated in the laser-induced CNV models and plays a pathogenic role in CNV. Blockade of Wnt signaling using an anti-LRP6 antibody has therapeutic potential in CNV.
authors.affiliation: Department of Physiology, University of Oklahoma, Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hu
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Mingkai
authors.initials: M
authors.lastname: Lin
authors.forename: Kyungwon
authors.initials: K
authors.lastname: Lee
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mott
authors.forename: Jian-xing
authors.initials: JX
authors.lastname: Ma
mesh_terms: D000367:Age Factors; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002460:Cell Line; D020256:Choroidal Neovascularization / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D007834:Lasers / Q000009:adverse effects; D008024:Ligands; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000037:antagonists & inhibitors / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D011914:Rats, Inbred BN; D011973:Receptors, LDL / Q000235:genetics; D055213:Retinal Pigment Epithelium / Q000166:cytology; D057135:Wet Macular Degeneration / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D008024:Ligands; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D011973:Receptors, LDL; C036053:VLDL receptor