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Eric Kunz, Colin Andrew Bretz, Vladimir Divoky, M Elizabeth Hartnett; Constitutive erythropoietin receptor signaling exacerbates pathologic choroidal neovascularization in an animal model. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2262. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Erythropoietin (EPO) is increasingly recognized for neuroprotective and angiogenic effects in addition to its well established role in hematopoiesis. What remains less clear is the role of EPO receptor (EPOR) signaling in the context of physiologic and pathologic neovascularization. We tested the hypothesis that EPOR signaling contributes to the development of pathologic angiogenesis using a laser-induced choroidal neovascularization (LCNV) model.
This study utilized 6-week old knock-in mice in which the mouse EPOR (mWtEPOR) gene was replaced with either the human EPOR (hWtEPOR) gene, resulting in decreased EPOR signaling, or a constitutively active human mutant EPOR (hMutEPOR) gene, resulting in increased EPOR signaling. The Phoenix micron IV laser module was used to create three laser-burns (450mW, 100ms) in the Bruch’s membrane of each eye roughly two disk diameters from the optic nerve head. Seven days post-laser treatment, choroids were dissected and stained with isolectin-B4 to visualize choroidal neovascularization. Z-stacks of each individual lesion were captured using a confocal microscope, and the lesion volume was calculated using IMARIS software as well as by hand. Each group contained an n of ≥ 40 lesions, data was normalized to the control mWtEPOR mice and analyzed using a one-way ANOVA.
Analysis of lesion volume 7 days after laser, revealed that the average lesion volume of hWtEPOR mice was 33.8 % smaller than that of control mWTEPOR mice (p = 0.0466), and that the average lesion in hMutEPOR mice was 30% larger compared to mWtEPOR (p = 0.0002).
In this study, transgenic hWtEPOR mice that have constitutively decreased EPOR signaling develop smaller CNV after laser-induced damage, whereas hMutEPOR mice that have constitutively active EPOR signaling develop larger CNV. These results support the hypothesis that EPOR signaling is important in the development of pathologic angiogenesis, and support previous studies by us and others that defined a role for EPO and EPOR signaling in retinal angiogenesis associated with oxygen induced retinopathy. Additional studies are indicated to understand the cell specific contributions of EPOR signaling in this context.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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