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17-Alpha-estradiol ameliorating oxygen-induced retinopathy in a murine model

  • Laboratory Investigation
  • Published:
Japanese Journal of Ophthalmology Aims and scope Submit manuscript

Abstract

Purpose

Our aim was to explore the effects and mechanism of 17-alpha-estradiol (17α-E2) on oxygen-induced retinopathy (OIR) in a murine model.

Methods

Newborn mice exposed to hyperoxia underwent subcutaneous injections of different doses of 17α-E2 from postnatal days (PND) 7 to 17. The retinal flat mounts were scored for avascular/total retinal area on PND 17. Vascular endothelial growth factor (VEGF), malondialdehyde (MDA) concentrations, and intensity, activity, and quality of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the retina were determined on PND 9, 13 (14), and 17.

Results

The avascular area, which is found in retinas of hyperoxia-exposed pups but not in retinas of normoxia-exposed ones, was significantly smaller in retinas of 17α-E2-treated pups. MDA and VEGF concentrations and intensity, activity, and quality of NADPH oxidase were stable in retinas of normoxia pups on PND 9, 13 (14), and 17, whereas in retinas of hyperoxia-exposed and 17α-E2-treated pups, they fluctuated markedly. VEGF concentrations were lower in retinas of hyperoxia-exposed pups than in those of normoxia ones on PND 9. Elevated VEGF concentrations were found in retinas of 17α-E2-treated pups on PND 9 and in hyperoxia-exposed pups on PND 14 and 17. Low VEGF concentrations were found in retinas of 17α-E2-treated pups on PND 14 and 17. MDA concentrations and NADPH oxidase concentration and activity, which were higher in retinas of hyperoxia-exposed pups, were lower in retinas of 17α-E2-treated pups on PND 9, 13, and 17. The most effective outcome in retinas of 1.0 μg 17α-E2-treated pups was markedly reversed by ICI182780.

Conclusions

We found that 17α-E2 mitigates oxidative stress reactions and ameliorates OIR severity by decreasing NADPH oxidase expression and activity via the receptor and other pathways.

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References

  1. Chen J, Smith LE. Retinopathy of prematurity. Angiogenesis. 2007;10:133–40.

    Article  PubMed  Google Scholar 

  2. Chen J, Stahl A, Hellstrom A, Smith LE. Current update on retinopathy of prematurity: screening and treatment. Curr Opin Pediatr. 2011;23:173–8.

    Article  PubMed  CAS  Google Scholar 

  3. Tulchinsky D, Osathanondh R, Belisle S, Ryan KJ. Plasma estrone, estradiol, estriol and their precursors in pregnancies with anencephalic fetuses. J Clin Endocrinol Metab. 1977;45:1100–3.

    Article  PubMed  CAS  Google Scholar 

  4. Saito Y, Geisen P, Uppal A, Hartnett ME. Inhibition of NAD(P)H oxidase reduces apoptosis and avascular retina in an animal model of retinopathy of prematurity. Mol Vis. 2007;13:840–53.

    PubMed  CAS  Google Scholar 

  5. Saito Y, Uppal A, Byfield G, Budd S, Hartnett ME. Activated NAD(P)H oxidase from supplemental oxygen induces neovascularization independent of VEGF in retinopathy of prematurity model. Invest Ophthalmol Vis Sci. 2008;49:1591–8.

    Article  PubMed  Google Scholar 

  6. Connor KM, SanGiovanni JP, Lofqvist C, Aderman CM, Chen J, Higuchi A, et al. Increased dietary intake of omega-3-poly-unsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med. 2007;13:868–73.

    Article  PubMed  CAS  Google Scholar 

  7. Brion LP, Bell EF, Raghuveer TS, Soghier L. What is the appropriate intravenous dose of vitamin E for very-low-birth-weight infants? J Perinatol. 2004;24:205–7.

    Article  PubMed  CAS  Google Scholar 

  8. Lee JW, Davis JM. Future applications of antioxidants in premature infants. Curr Opin Pediatr. 2011;23:161–6.

    Article  PubMed  CAS  Google Scholar 

  9. Hartnett ME. The effects of oxygen stresses on the development of features of severe retinopathy of prematurity: knowledge from the 50/10 OIR model. Doc Ophthalmol. 2010;120:25–39.

    Article  PubMed  Google Scholar 

  10. Miller AA, Drummond GR, Mast AE, Schmidt HH, Sobey CG. Effect of gender on NADPH-oxidase activity, expression, and function in the cerebral circulation: role of estrogen. Stroke. 2007;38:2142–9.

    Article  PubMed  CAS  Google Scholar 

  11. Sumi D, Hayashi T, Matsui-Hirai H, Jacobs AT, Ignarro LJ, Iguchi A. 17 beta-estradiol inhibits NADPH oxidase activity through the regulation of p47 phox mRNA and protein expression in THP-1 cells. Biochim Biophys Acta. 2003;1640:113–8.

    Article  PubMed  CAS  Google Scholar 

  12. Zhang QG, Raz L, Wang R, Han D, De Sevilla L, Yang F, et al. Estrogen attenuates ischemic oxidative damage via an estrogen receptor alpha-mediated inhibition of NADPH oxidase activation. Neuroscience. 2009;29:13823–36.

    Article  PubMed  CAS  Google Scholar 

  13. Ortmann J, Veit M, Zingg S, Di Santo S, Traupe T, Yang Z, et al. Estrogen receptor-α but not -β or GPER inhibits high glucose-induced human VSMC proliferation: potential role of ROS and ERK. J Clin Endocrinol Metab. 2011;96:220–8.

    Article  PubMed  Google Scholar 

  14. Miyamoto N, Mandai M, Takagi H, Suzuma I, Suzuma K, Koyama S, et al. Contrasting effect of estrogen on VEGF induction under different oxygen status and its role in murine ROP. Invest Ophthalmol Vis Sci. 2002;43:2007–14.

    PubMed  Google Scholar 

  15. Smith LE, Wesolowski E, McLellan A, Kostyk SK, D’Amato R, Sullivan R, et al. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci. 1994;35:101–11.

    PubMed  CAS  Google Scholar 

  16. D’Amato R, Wesolowski E, Smith LE. Microscopic visualization of retina by angiography with high-molecular-weight fluorescein-labeled dextrans in the mouse. Microvasc Res. 1993;46:135–42.

    Article  PubMed  Google Scholar 

  17. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95:351–8.

    Article  PubMed  CAS  Google Scholar 

  18. Rinaldi Tosi ME, Bocanegra V, Manucha W, Gil Lorenzo A, Vallés PG. The Nrf2-Keap1 cellular defense pathway and heat shock protein 70 (Hsp70) response. Role in protection against oxidative stress in early neonatal unilateral ureteral obstruction (UUO). Cell Stress Chaperones. 2011;16:57–68.

    Google Scholar 

  19. Souvannakitti D, Nanduri J, Yuan G, Kumar GK, Fox AP, Prabhakar NR. NADPH oxidase-dependent regulation of T-type Ca2+ channels and ryanodine receptors mediate the augmented exocytosis of catecholamines from intermittent hypoxia-treated neonatal rat chromaffin cells. J Neurosci. 2010;30:10763–72.

    Article  PubMed  CAS  Google Scholar 

  20. Hartnett ME. Studies on the pathogenesis of avascular retina and neovascularization into the vitreous in peripheral severe retinopathy of prematurity (an american ophthalmological society thesis). Trans Am Ophthalmol Soc. 2010;108:96–119.

    PubMed  Google Scholar 

  21. Stahl A, Connor KM, Sapieha P, Willett KL, Krah NM, Dennison RJ, et al. Computer-aided quantification of retinal neovascularization. Angiogenesis. 2009;12:297–301.

    Article  PubMed  CAS  Google Scholar 

  22. Huang H, Shen J, Vinores SA. Blockade of VEGFR1 and 2 suppresses pathological angiogenesis and vascular leakage in the eye. PLoS ONE. 2011;6:e21411.

    Article  PubMed  CAS  Google Scholar 

  23. Roohipoor R, Ghasemi H, Ghassemi F, Karkhaneh R, Riazi-Esfahani M, Nili-Ahmadabadi M. Intravitreal bevacizumab in retinopathy of prematurity: an interventional case series. Graefes Arch Clin Exp Ophthalmol. 2011;249:1295–301.

    Article  PubMed  CAS  Google Scholar 

  24. Kusari J, Padillo E, Zhou SX, Bai Y, Wang J, Song Z, et al. Effect of brimonidine on retinal and choroidal neovascularization in a mouse model of retinopathy of prematurity and laser-treated rats. Invest Ophthalmol Vis Sci. 2011;52:5424–31.

    Article  PubMed  CAS  Google Scholar 

  25. Lutty GA, McLeod DS, Bhutto I, Wiegand SJ. Effect of VEGF trap on normal retinal vascular development and oxygen-induced retinopathy in the dog. Invest Ophthalmol Vis Sci. 2011;52:4039–47.

    Article  PubMed  CAS  Google Scholar 

  26. Xu Y, Zhao H, Zheng Y, Gu Q, Ma J, Xu X. A novel antiangiogenic peptide derived from hepatocyte growth factor inhibits neovascularization in vitro and in vivo. Mol Vis. 2010;16:1982–95.

    PubMed  CAS  Google Scholar 

  27. Wu WC, Yeh PT, Chen SN, Yang CM, Lai CC, Kuo HK. Effects and complications of bevacizumab use in patients with retinopathy of prematurity: a multicenter study in Taiwan. Ophthalmology. 2011;118:176–83.

    Article  PubMed  Google Scholar 

  28. Drenser KA. Anti-angiogenic therapy in the management of retinopathy of prematurity. Dev Ophthalmol. 2009;44:89–97.

    Article  PubMed  CAS  Google Scholar 

  29. Yang CS, Wang AG, Sung CS, Hsu WM, Lee FL, Lee SM. Long-term visual outcomes of laser-treated threshold retinopathy of prematurity: a study of refractive status at 7 years. Eye (Lond). 2010;24:14–20.

    Article  Google Scholar 

  30. Zhang W, Yokota H, Xu Z, Narayanan SP, Yancey L, Yoshida A, et al. Hyperoxia therapy of pre-proliferative ischemic retinopathy in a mouse model. Invest Ophthalmol Vis Sci. 2011;52:6384–95.

    Article  PubMed  CAS  Google Scholar 

  31. Lange C, Ehlken C, Stahl A, Martin G, Hansen L, Agostini HT. Kinetics of retinal vaso-obliteration and neovascularisation in the oxygen-induced retinopathy (OIR) mouse model. Graefes Arch Clin Exp Ophthalmol. 2009;247:1205–11.

    Article  PubMed  CAS  Google Scholar 

  32. Dong A, Xie B, Shen J, Yoshida T, Yokoi K, Hackett SF, et al. Oxidative stress promotes ocular neovascularization. J Cell Physiol. 2009;219:544–52.

    Article  PubMed  CAS  Google Scholar 

  33. Toran-Allerand CD, Tinnikov AA, Singh RJ, Nethrapalli IS. 17alpha- estradiol: a brain-active estrogen? Endocrinology. 2005;146(9):3843–50.

    Article  PubMed  CAS  Google Scholar 

  34. McClean J, Nuñez JL. 17 alpha-Estradiol is neuroprotective in male and female rats in a model of early brain injury. Exp Neurol. 2008;210(1):41–50.

    Article  PubMed  CAS  Google Scholar 

  35. Yi KD, Cai ZY, Covey DF, Simpkins JW. Estrogen receptor-independent neuroprotection via protein phosphatase preservation and attenuation of persistent extracellular signal-regulated kinase 1/2 activation. J Pharmacol Exp Ther. 2008;324(3):1188–95.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Ophthalmology, The Second Affiliated Hospital of Xi’an Jiaotong University, #157 Xiwu Road, Xi’an, 710004, Shanxi, People’s Republic of China

    Hong-Bing Zhang & Nai-Xue Sun

  2. Eye Institute of Shanxi Province and Xi’an Eye Hospital, #30 Fenxiang, Nanda Avenue, Xi’an, 710002, People’s Republic of China

    Hong-Bing Zhang, Hou-Cheng Liang, Xiang-Hua Xiao, Xian-Ning Liu & Ya-Ni Wang

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  1. Hong-Bing Zhang
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  4. Xiang-Hua Xiao
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Correspondence to Nai-Xue Sun.

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Zhang, HB., Sun, NX., Liang, HC. et al. 17-Alpha-estradiol ameliorating oxygen-induced retinopathy in a murine model. Jpn J Ophthalmol 56, 407–415 (2012). https://doi.org/10.1007/s10384-012-0136-5

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  • DOI: https://doi.org/10.1007/s10384-012-0136-5

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