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Colin A Bretz, Haibo Wang, Silke Becker, Vladimir Divoky, M Elizabeth Hartnett; Erythropoietin receptor signaling contributes to the development of pathologic retinal angiogenesis. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3641.
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© ARVO (1962-2015); The Authors (2016-present)
Erythropoietin (EPO), known for its hematopoietic effects, is being considered as a neuroprotective agent in both diabetic patients and premature infants. However, in some reports EPO signaling has been linked with pathologic intravitreal neovascularization (IVNV) in retinopathy of prematurity (ROP), raising concerns about EPO use in at risk populations. As a result, we tested the hypothesis that increased EPO receptor (EPOR) signaling contributes to pathologic angiogenesis by comparing outcomes between knock-in mice in which the mouse EPOR (mEPOR) gene was replaced with the human EPOR gene (hEPOR), resulting in less efficient, and therefore, reduced EPOR signaling, and wild type mice with normal EPOR signaling, in a model of oxygen-induced retinopathy (OIR).
Postnatal day 7 (p7) hEPOR and mEPOR mice were placed into 75% oxygen for 5 days and removed to room air on postnatal day 12 (p12). Retinal flat mounts were prepared and stained with isolectin to visualize vascularization at p12 and postnatal day 17 (p17). Stained flat mounts were captured using a confocal microscope and images were analyzed to determine the amount of avascular area (AVA) at p12 and p17 and intravitreal neovascularization (IVNV) at p17. Data is provided as a fold change relative to control mice and was analyzed using a one-way ANOVA.
Analysis of retinal flat mounts at p12 revealed a 1.3-fold increase in AVA of hEPOR mice compared to wild type mEPOR controls (p<0.001). At p17, hEPOR retinal flat mounts had a 3.2-fold increase in AVA compared to control mice (p<0.001), but a 3.7-fold decrease in IVNV when compared to control mice (p<0.001).
This study supports the hypothesis that EPOR signaling is important in angiogenesis and appears important in both physiologic and hypoxia-induced pathologic intravitreal neovascularization as shown by increased AVA and reduced IVNV in the knock-in hEPOR mice compared to mEPOR mice. It also supports previous studies that found that EPO ligand given prior to hyperoxia stabilized vasculature, but led to worse IVNV when given at a later timepoint. Additional studies are indicated to understand the downstream effects of EPOR signaling.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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