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J. Chen, C. M. Aderman, K. M. Connor, O. P. Aspegren, K. L. Willett, L. E. H. Smith; Intervention of Erythropoietin in Proliferative Retinopathy in Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5439. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Proliferative retinopathies, including retinopathy of prematurity and diabetic retinopathy, are leading causes of blindness in children and working age adults. These diseases are characterized by an initial vessel loss phase followed by a hypoxia-induced neovascularization phase. Erythropoietin (Epo), an oxygen-regulated growth factor, is suppressed in the vessel loss phase and up-regulated in the proliferation phase of retinopathy. Since Epo is a common anemia treatment used widely in patients with retinopathies, we studied the specific effects of Epo intervention during the two phases of retinopathy in a mouse model of oxygen-induce retinopathy.
To induce retinopathy, neonatal mice were exposed to 75% oxygen from P7 to P12, followed by room air until P17, when the retina is flat-mounted with lectin staining to visualized vessels. Recombinant Epo or PBS control was injected intraperitoneally to mice littermates prior to and during oxygen exposure, or after returning to room air. Intravitreal injection of Epo siRNA or control siRNA was carried out after oxygen exposure to fellow eyes of same animal. Gene expression of Epo-treated retinas was analyzed with microarray. Caspase activity was measured in retinal lysate from Epo-treated mice and retinal NF-ΚB level was measured with an NF-ΚB-luciferase reporter mouse.
Early Epo treatment in the first phase of retinopathy significantly reduced retinal vessel loss and pathological neovascularization as well as neuronal apoptosis at P17 compared with PBS control. In contrast, Epo treatment in the second phase did not protect retina vasculature with a trend to enhanced pathological neovascularization. Inhibition of Epo with siRNA in the second phase protected retina vessels from neovascularization. Epo treatment in the first phase increased the number of bone-marrow derived pro-angiogenic cells in the retina to promote vessel repair. In addition, early Epo also protects retina through local pathways as revealed by gene expression using microarray, including NF-ΚB and caspase. Early Epo treatment increased the protein level of NF-ΚB, a pro-survival factor, and suppressed caspase enzymatic activity, a pro-apoptotic protein.
Early supplement of Epo during the first phase of retinopathy protects retina from vessel loss and pathological proliferation, while as in the second phase of retinopathy, inhibiting Epo is beneficiary. These results suggest that timing of Epo intervention is critical for patients with proliferative retinopathy.
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