title: 17β-estradiol ameliorates oxygen-induced retinopathy in the early hyperoxic phase.
abstract: Retinopathy of prematurity (ROP) is a major and leading cause of blindness in premature infants. It has been realized that early treatment for ROP is important. However, all the early treatments of ROP are focusing on peripheral retinal ablation which does not surmount the limit of extinguishing retinal neovascularization and protecting the retinas of children with ROP from the injury of ablation. In this study, we investigated the morphological changes of retina and oxidative stress alterations in the early phase of oxygen-induced retinopathy (OIR) and tested the effects of 17β-estradiol (17β-E2), a nonselective estrogen receptor (ER) agonist, on early phase OIR development. We found that large central capillary-free areas were induced in the retinas of pups exposed to hyperoxia on postnatal day 9 (P9), whereas vascularization was almost complete in the retinas of pups exposed to normoxia at the same age. The concentrations of malondiadehyde (MDA), an end-product of oxidative stress, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a major enzyme producing free radicals, as well as the activity of NADPH oxidase were significantly elevated in the retinas of pups exposed to hyperoxia on P9 and postnatal day 13 (P13) compared to those in age matched pups exposed to normoxia. Treatment with 17β-E2 decreased not only the percentage of the central capillary-free area to total retina area but also the concentrations of MDA and NADPH oxidase as well as the activity of NADPH oxidase in a dose-dependent manner in pups exposed to hyperoxia on p9 and P13. The concentration of VEGF was significantly decreased on P9 but increased on P14 in the retinas of pups exposed to hyperoxia, whereas it was significantly elevated on P9 but decreased on P14 in the retinas of pups treated with 17β-E2. The effect of 17β-E2 could be reversed by the co-treatment with ICI182780, a high affinity estrogen receptor antagonist, which suggested that 17β-E2 might exert its effect on early hyperoxic phase of OIR through estrogen receptor. Our results suggest that treatment with antioxidant drugs at early hyperoxic phase of ROP even before the appearance of retinal neovascularization may be more effective than their application to ROP at late phase, which may abolish the deleterious factors that contribute to retinal neovascularization and promote retinal blood vessels to develop healthily.
authors.affiliation: Eye Institute of Shaanxi Province and Xi'an First Hospital, #30, Fenxiang, Nanda Avenue, Xi'an 710002, PR China. Electronic address: zhanghongbing01@163.com.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Eye Institute of Shaanxi Province and Xi'an First Hospital, #30, Fenxiang, Nanda Avenue, Xi'an 710002, PR China; Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Eye Institute of Shaanxi Province and Xi'an First Hospital, #30, Fenxiang, Nanda Avenue, Xi'an 710002, PR China.
authors.forename: Kun
authors.initials: K
authors.lastname: Xu
authors.affiliation: Eye Institute of Shaanxi Province and Xi'an First Hospital, #30, Fenxiang, Nanda Avenue, Xi'an 710002, PR China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Eye Institute of Shaanxi Province and Xi'an First Hospital, #30, Fenxiang, Nanda Avenue, Xi'an 710002, PR China.
authors.forename: Yani
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Eye Institute of Shaanxi Province and Xi'an First Hospital, #30, Fenxiang, Nanda Avenue, Xi'an 710002, PR China.
authors.forename: Xianning
authors.initials: X
authors.lastname: Liu
authors.affiliation: Eye Institute of Shaanxi Province and Xi'an First Hospital, #30, Fenxiang, Nanda Avenue, Xi'an 710002, PR China.
authors.forename: Xianjiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Eye Institute of Shaanxi Province and Xi'an First Hospital, #30, Fenxiang, Nanda Avenue, Xi'an 710002, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA. Electronic address: xli3@kumc.edu.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D004958:Estradiol / Q000627:therapeutic use*; D004967:Estrogens / Q000627:therapeutic use*; D018496:Hyperoxia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D004967:Estrogens; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol; D019255:NADPH Oxidases; D010100:Oxygen
keywords: 17β-estradiol; NADPH oxidase; Oxidative stress; Oxygen-induced retinopathy; Receptor