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J. Chen, C. M. Aderman, K. M. Connor, N. Liu, A. Higuchi, L. E. H. Smith; Erythropoietin Protects Retina From Pathological Vessel Loss and Subsequent Proliferation. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1963.
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Erythopoietin (Epo), a hypoxia-induced growth factor that regulates erythrocyte production, is widely administered for treatment of anemia in patients with retinopathies. Many retinopathies, including retinopathy of prematurity and diabetic retinopathy, are characterized by an initial vessel loss phase followed by a hypoxia-induced proliferation phase. Given the recent evidence showing that Epo is a potent angiogenic and cytoprotective factor, determining the effect of Epo intervention during the two phases of retinopathy is of great clinical interest and significance.
Retinopathy was induced in neonatal mice by exposing them to 75% oxygen from P7 to P12, followed by room air until P17. Recombinant Epo or PBS control was injected systemically to mouse littermates prior to and during oxygen exposure, or after returning to room air. The effect of Epo on vessel loss and neovascularization (NV) was analyzed on P8 retinal flat mount after FITC perfusion, and P17 flat mount with lectin staining to visualized vessels. The effect of Epo on neuronal survival was also examined with TUNEL stain on retinal cross sections.
Injection of Epo (P6 and P7) decreased the initial vessel loss (P8) by ~20% in a dose dependent manner (P<0.01). At P17, early Epo injection during oxygen exposure (P6-P12) reduced non-vascularized area by ~50% (P<0.001), and pathological NV by ~30% (P<0.02) (n=40 and 23 for Epo and PBS respectively). In contrast, injection of Epo after oxygen exposure (P14-16) does not reduce either vessel loss or NV. Early Epo injection also significantly protected retinal neurons from apoptosis. It is likely that Epo protects retina vessels through increasing the number of bone-marrow derived progenitor cells in the retina, including endothelial progenitor cells and microglia, which can help promote vessel repair.
In this study we observed that early administration of Epo prevented initial retinal vessel loss and inhibited subsequent pathological proliferation, while late injection of Epo did not. These data suggest that Epo intervention could be beneficial for treating retinopathies and timing is critical in designing the therapy.
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