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J. Chen, N. Liu, Z. Kachara, C.M. Aderman, K.M. Connor, L.E. H. Smith; Early Administration of Erythropoietin Prevents Oxygen–Induced Retinal Vascular Degeneration in Retinopathy of Prematurity . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3219.
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Erythopoietin(Epo) is considered to be a systemic growth factor which regulates erythrocyte production and is widely administered for treatment of anaemia in patients including premature neonates. However Epo has been found recently to be important also as a hypoxia–regulated angiogenic factor. Oxygen supplementation in premature neonates can induce retinopathy of prematurity (ROP) with hyperoxia–induced retinal vessel loss followed by hypoxia–induced pathological vessel proliferation. There is evidence suggesting Epo is a potent angiogenic factor that contributes to proliferative retinopathy, however, the effect of Epo on vascular loss is not known. Does suppression of Epo with oxygen contribute to vascular instability?
To investigate the role of Epo in ROP, we used a mouse model of oxygen–induced retinopathy with neonatal mice exposed to 75% oxygen from P7 to P12 and room air exposure until P17. Retinal RNA was isolated from 6 mice at different time points during the induction of ROP. Epo or control was injected systemically in 6 mice at each various time points after birth. Retinal vessel loss and neovascularization were examined in retinal flat mount.
Retinal Epo mRNA expression was suppressed (> 5 fold) during hyperoxia treatment (P8–P12) and increased dramatically (>10 fold at P15) after induction of hypoxia after returning to room air. Injection of Epo to animals prior to hyperoxia treatment (P6 and P7) decreased hyperoxia–induced retinal vaso–obliteration (P8) in a dose dependent manner. Moreover, early injection of Epo to animals prior to and during oxygen exposure (P6–12) significantly reduced retinal neovascularization at P17. In contrast, injection of Epo after oxygen exposure (P14–16) does not protect retina from neovascularization.
These findings suggest that oxygen–induced suppression of retinal Epo mRNA expression contributes in part to the development of ROP by suppressing vascular survival. Epo treatment prior to or during vascular loss may help prevent the late stage neovacularization of ROP whereas treatment during neovascularization may exacerbate disease.
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