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Norihiro Nagai, Kanako Izumi-Nagai, Scott Robbie, James W. Bainbridge, Bo Chang, Ronald Hurd, Yin-shan Ng, David T. Shima; Spontaneous Cnv In A Novel Mutant Mouse Is Associated With Early Chorio-retinal Para-inflammation And Vegf Driven Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1015.
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The mutant mouse strain JR5558 exhibits early, reproducible and spontaneous bi-lateral choroidal neovascularization (CNV), accompanied by subsequent retinal anastamosis. Here we explore the hypothesis that chorio-retinal para-inflammation triggers neuroglial dysfunction and VEGF-driven CNV.
Signalling, leukocytes and inflammatory molecules were analyzed by immunostaining, ELISA, qPCR and western blotting. Photoreceptor loss was estimated by measuring ONL and retina thickness. Permeability of choriocapillaris and retinal vessels was analyzed using fluorescent dextran tracers. Pharmacological blockade of candidate signaling molecules was performed by intraperitoneal injections daily from P14 to P24 and CNV development was evaluated by fluorescein angiography and immunostaining.
We determined that the JR5558 CNV was not due to changes in Wnt- signalling, which has been implicated in CNV observed in the VLDLR deficient mouse. Development of each CNV lesion was accompanied by F4/80 positive macrophage, thus we focused on inflammatory pathways. NF-ΚB p65 was translocated into the nucleus of RPE and neovascular cells and I-ΚB was degraded, indicating activation of the NF-ΚB pathway. CCL11 and CCL 24 were present in neovascular tissue and retinal and RPE-choroidal expression of CCL11 and CCL24 were significantly higher in JR5558 mice than in age-matched controls. Leakage of dextran from choriocapillaris was increased in the JR5558 mice as was the presence of perivascular myeloid cells. VEGF-A levels were elevated in the choriocapillaris and RPE just prior to CNV formation, and CNV was dose-dependently suppressed using a VEGFR-2 blocking antibody.
We have demonstrated that chorio-retinal para-inflammation is present prior to frank CNV, and is associated with upregulation of VEGF, hyper-permeability of the choriocapillaris and neuroglial cell loss/dysfunction. Elucidation of the genetic basis of CNV in this model, as well as use of the model in target validation pharmacology will be important for the discovery of new therapeutics for neovascular AMD.
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