Long-lasting impairments in rodent oxygen-induced retinopathy measured by retinal vessel density and visual function

  • Xu Wang
  • Ke Shen
  • Fang Lu
  • Shigang HeEmail author
Research Paper


In mild or moderate retinopathy of prematurity (ROP), retinal vessels undergo obliteration, proliferation, and regression. Despite complete regression of vessel abnormalities, a variety of visual impairments have been reported. Rodent oxygen-induced retinopathy (OIR) is widely used as a model to study ROP. However, the long-term changes of OIR model remain unclear. The aim of this study is to examine long term changes of retinal vessel and visual function in a rodent OIR model resembling human mild or moderate ROP. In this study, after subjecting the animals to 80% oxygen (O2) for 5–7 d, the retinal vessel density at postnatal day 12 (P12) was approximately 30% lower than that in the age-matched control, but this difference was not significant between the groups. Vessel abnormalities, such as vessel tortuosity, neovascular tufts, and the number of vessels protruding into the vitreous, peaked between P17 and P20. Despite the regression of many abnormalities, vessel density in the OIR group was 36% and 32% lower than that in the control animals at 6 weeks and 4 months, respectively. The visual acuity and contrast sensitivity were impaired in the OIR group when measured at 2, 3 and 4 months. Therefore, the rodent OIR model exhibited long-lasting reduction in retinal vessel density and visual impairments, similar to those observed in mild or moderate human ROP. This study suggests that the rodent OIR model can be used to explore possible interventions for mild and moderate human ROP.


oxygen-induced retinopathy vessel plasticity visual acuity contrast sensitivity rat 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



This work was supported by the National Natural Science Foundation of China Key Project (31030036) to SH, a National Natural Science Foundation of China Project (81570863) and Science and Technology Supporting Program by Department of Science and Technology, Sichuan Province (2016SZ0024) to FL. We would like to thank Ms. Jiaying Ju for technical support.


  1. Arámbulo, O., Dib, G., Iturralde, J., Duran, F., Brito, M., and Fortes Filho, J.B. (2015). Intravitreal ranibizumab as a primary or a combined treatment for severe retinopathy of prematurity. Clin Ophthalmol 19, 2027–2032.Google Scholar
  2. Bossi, E., and Koerner, F. (1995). Retinopathy of prematurity. Intensive Care Med 21, 241–246.CrossRefGoogle Scholar
  3. Chen, M., Weng, S., Deng, Q., Xu, Z., and He, S. (2009). Physiological properties of direction-selective ganglion cells in early postnatal and adult mouse retina. J Physiol 587, 819–828.CrossRefGoogle Scholar
  4. Chung, E.J., Kim, J.H., Ahn, H.S., and Koh, H.J. (2007). Combination of laser photocoagulation and intravitreal bevacizumab (Avastin®) for aggressive zone I retinopathy of prematurity. Graefe’s Arch Clin Exp Ophthalmol 245, 1727–1730.CrossRefGoogle Scholar
  5. Connor, K.M., Krah, N.M., Dennison, R.J., Aderman, C.M., Chen, J., Guerin, K.I., Sapieha, P., Stahl, A., Willett, K.L., and Smith, L.E.H. (2009). Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat Protoc 4, 1565–1573.CrossRefGoogle Scholar
  6. Cryotherapy for Retinopathy of Prematurity Cooperative Group. (1988). Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol 106, 471–479.Google Scholar
  7. Dembinska, O., Rojas, L.M., Chemtob, S., Lachapelle, P. (2002). Evidence for a brief period of enhanced oxygen susceptibility in the rat model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 43, 2481–2490.Google Scholar
  8. Diao, L., Sun, W., Deng, Q., and He, S. (2004). Development of the mouse retina: emerging morphological diversity of the ganglion cells. J Neurobiol 61, 236–249.CrossRefGoogle Scholar
  9. Dobson, V., Quinn, G.E., Abramov, I., Hardy, R.J., Tung, B., Siatkowski, R. M., Phelps D.L. (1996). Color vision measured with pseudoisochromatic plates at five-and-a-half years in eyes of children from the CRYOROP study. Invest Ophthalmol Vis Sci 37, 2467–2474.Google Scholar
  10. Fielder, A.R., and Reynolds, J.D. (2001). Retinopathy of prematurity: clinical aspects. Semin Neonatol 6, 461–475.CrossRefGoogle Scholar
  11. Fisher, L.J. (1979). Development of synaptic arrays in the inner plexiform layer of neonatal mouse retina. J Comp Neurol 187, 359–372.CrossRefGoogle Scholar
  12. Flynn, J.T., O'Grady, G.E., Herrera, J., Kushner, B.J., Cantolino, S., and Milam, W. (1977). Retrolental fibroplasia: I. clinical observations. Arch Ophthalmol 95, 217–223.CrossRefGoogle Scholar
  13. Gibson, D.L., Sheps, S.B., Uh, S.H., Schechter, M.T., McCormick, A.Q. (1990). Retinopathy of prematurity-induced blindness: birth weightspecific survival and the new epidemic. Pediatrics 86, 405–412.Google Scholar
  14. Gilbert, C. (2008). Retinopathy of prematurity: a global perspective of the epidemics, population of babies at risk and implications for control. Early Human Dev 84, 77–82.CrossRefGoogle Scholar
  15. Hammer, D.X., Iftimia, N.V., Ferguson, R.D., Bigelow, C.E., Ustun, T.E., Barnaby, A.M., and Fulton, A.B. (2008). Foveal fine structure in retinopathy of prematurity: an adaptive optics Fourier domain optical coherence tomography study. Invest Ophthalmol Vis Sci 49, 2061–2070.CrossRefGoogle Scholar
  16. Hansen, R.M., Fulton, A.B. (2000). Background adaptation in children with a history of mild retinopathy of prematurity. Invest Ophthalmol Vis Sci 41, 320–324.Google Scholar
  17. Hartnett, M.E. (2015). Pathophysiology and mechanisms of severe retinopathy of prematurity. Ophthalmology 122, 200–210.CrossRefGoogle Scholar
  18. Hartnett, M.E., and Penn, J.S. (2012). Mechanisms and management of retinopathy of prematurity. N Engl J Med 367, 2515–2526.CrossRefGoogle Scholar
  19. Hellström, A., Smith, L.E., and Dammann, O. (2013). Retinopathy of prematurity. Lancet 382, 1445–1457.CrossRefGoogle Scholar
  20. Hunter, D.G., and Mukai, S. (1992). Retinopathy of prematurity: pathogenesis, diagnosis, and treatment. Int Ophthalmol Clin 32, 163–184.CrossRefGoogle Scholar
  21. Larsson, E., Rydberg, A., and Holmström, G. (2006). Contrast sensitivity in 10 year old preterm and full term children: a population based study. Brit J Ophthalmol 90, 87–90.CrossRefGoogle Scholar
  22. Lue, C.L., Hansen, R.M., Reisner, D.S., Findl, O., Petersen, R.A., and Fulton, A.B. (1995). The course of myopia in children with mild retinopathy of prematurity. Vision Res 35, 1329–1335.CrossRefGoogle Scholar
  23. Matsubara, M., Saito, Y., Nakanishi-Ueda, T., Ueda, T., Hisamitsu, T., Koide, R., and Takahashi, H. (2014). Influence of the difference of breastfeeding volume on a rat model of oxygen-induced retinopathy. J Clin Biochem Nutr 55, 129–134.CrossRefGoogle Scholar
  24. Mintz-Hittner, H.A., Kennedy, K.A., Chuang, A.Z., and Chuang, A.Z. (2011). Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 364, 603–615.CrossRefGoogle Scholar
  25. Moskowitz, A., Hansen, R., and Fulton, A. (2005). Early ametropia and rod photoreceptor function in retinopathy of prematurity. Optom Vis Sci 82, 307–317.CrossRefGoogle Scholar
  26. O’Connor, A.R., Stephenson, T., Johnson, A., Tobin, M.J., Moseley, M.J., Ratib, S., Ng, Y., and Fielder, A.R. (2002). Long-term ophthalmic outcome of low birth weight children with and without retinopathy of prematurity. Pediatrics 109, 12–18.CrossRefGoogle Scholar
  27. O’Connor, A.R., Stephenson, T.J., Johnson, A., Tobin, M.J., Ratib, S., Moseley, M., and Fielder, A.R. (2004). Visual function in low birthweight children. Brit J Ophthalmol 88, 1149–1153.CrossRefGoogle Scholar
  28. Penn, J.S., Henry, M.M., and Tolman, B.L. (1994a). Exposure to alternating hypoxia and hyperoxia causes severe proliferative retinopathy in the newborn rat. Pediatr Res 36, 724–731.CrossRefGoogle Scholar
  29. Penn, J.S., Henry, M.M., Wall, P.T., Tolman, B.L. (1995). The range of PaO2 variation determines the severity of oxygen-induced retinopathy in newborn rats. Invest Ophthalmol Vis Sci 36, 2063–2070.Google Scholar
  30. Penn, J.S., Tolman, B.L., Henry, M.M. (1994b). Oxygen-induced retinopathy in the rat: relationship of retinal nonperfusion to subsequent neovascularization. Invest Ophthalmol Vis Sci 35, 3429–3435.Google Scholar
  31. Penn, J.S., Tolman, B.L., Lowery, L.A. (1993). Variable oxygen exposure causes preretinal neovascularization in the newborn rat. Invest Ophthalmol Vis Sci 34, 576–585.Google Scholar
  32. Prusky, G.T., West, P.W.R., and Douglas, R.M. (2000). Behavioral assessment of visual acuity in mice and rats. Vision Res 40, 2201–2209.CrossRefGoogle Scholar
  33. Reisner, D.S., Hansen, R.M., Findl, O., Petersen, R.A., Fulton, A.B. (1997). Dark-adapted thresholds in children with histories of mild retinopathy of prematurity. Invest Ophthalmol Vis Sci 38, 1175–1183.Google Scholar
  34. Ren, L., Liang, H., Diao, L., and He, S. (2010). Changing dendritic field size of mouse retinal ganglion cells in early postnatal development. Devel Neurobiol 70, 397–407.CrossRefGoogle Scholar
  35. Ren, R., Li, Y., Liu, Z., Liu, K., and He, S. (2012). Long-term rescue of rat retinal ganglion cells and visual function by AAV-mediated BDNF expression after acute elevation of intraocular pressure. Invest Ophthalmol Vis Sci 53, 1003–1011.CrossRefGoogle Scholar
  36. Reynaud, X., Vallat, M., Vincent, D., Dorey, C.K. (1991). Protective effect of the Ginkgo biloba extract in the rat model of retinopathy of prematurity (ROP). Invest Ophthalmol Vis Sci 32. 1147.Google Scholar
  37. Ricci, B., Ricci, F., and Maggiano, N. (2000). Oxygen-induced retinopathy in the newborn rat: morphological and immunohistological findings in animals treated with topical timolol maleate. Ophthalmologica 214, 136–139.CrossRefGoogle Scholar
  38. Ridler, T.W., Calvard, S. (1978). Picture thresholding using an iterative selection method. In: IEEE Systems, Man, and Cybernetics Society 8, 630–632.Google Scholar
  39. Schneider, C.A., Rasband, W.S., and Eliceiri, K.W. (2012). NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9, 671–675.CrossRefGoogle Scholar
  40. Shah, P.K., Narendran, V., Tawansy, K.A., Raghuram, A., and Narendran, K. (2007). Intravitreal bevacizumab (Avastin) for post laser anterior segment ischemia in aggressive posterior retinopathy of prematurity. Ind J Ophthalmol 55, 75–76.CrossRefGoogle Scholar
  41. Shih, S.C., Ju, M., Liu, N., and Smith, L.E.H. (2003). Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity. J Clin Invest 112, 50–57.CrossRefGoogle Scholar
  42. Smith, L.E., Wesolowski, E., McLellan, A., Kostyk, S.K., D’Amato, R., Sullivan, R., et al. (1994). Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 35, 101–111.Google Scholar
  43. Steinkuller, P.G., Du, L., Gilbert, C., Foster, A., Collins, M.L., and Coats, D.K. (1999). Childhood blindness. J Aapos 3, 26–32.CrossRefGoogle Scholar
  44. Sun, L., Han, X., and He, S. (2011). Direction-selective circuitry in rat retina develops independently of GABAergic, cholinergic and action potential activity. PLoS ONE 6, e19477.CrossRefGoogle Scholar
  45. Tasman, W. (1986). A pilot study on cryotherapy and active retinopathy of prematurity. Graefe’s Arch Clin Exp Ophthalmol 224, 201–202.CrossRefGoogle Scholar
  46. Tasman, W., and Brown, G.C. (1989). Progressive visual loss in adults with retinopathy of prematurity (ROP). Graefe’s Arch Clin Exp Ophthalmol 227, 309–311.CrossRefGoogle Scholar
  47. Tasman, W., Brown, G.C., Naidoff, M., Schaffer, D.B., Benson, W., Quinn, G., and Diamond, G. (1987). Cryotherapy for active retinopathy of prematurity. Graefe’s Arch Clin Exp Ophthalmol 225, 3–4.CrossRefGoogle Scholar
  48. Tian, N., and Copenhagen, D.R. (2001). Visual deprivation alters development of synaptic function in inner retina after eye opening. Neuron 32, 439–449.CrossRefGoogle Scholar
  49. Ventresca, M.R., Gonder, J.R., Tanswell, A.K. (1990). Oxygen-induced proliferative retinopathy in the newborn rat. Can J Ophthalmol 25, 186–189.Google Scholar
  50. Weng, S., Sun, W., and He, S. (2005). Identification of ON-OFF directionselective ganglion cells in the mouse retina. J Physiol 562, 915–923.CrossRefGoogle Scholar
  51. Xu, H., and Tian, N. (2004). Pathway-specific maturation, visual deprivation, and development of retinal pathway. Neuroscientist 10, 337–346.CrossRefGoogle Scholar
  52. Xue, J., and Cooper, N.G.F. (2001). The modification of NMDA receptors by visual experience in the rat retina is age dependent. Mol Brain Res 91, 196–203.CrossRefGoogle Scholar
  53. Yang, X.L., Shi, X.M., and He, S.G. (2010). Properties of mouse retinal ganglion cell dendritic growth during postnatal development. Sci China Life Sci 53, 669–676.CrossRefGoogle Scholar
  54. Yi, Z., Su, Y., Zhou, Y., Zheng, H., Ye, M., Xu, Y., and Chen, C. (2015). Effects of intravitreal ranibizumab in the treatment of retinopathy of prematurity in chinese infants. Curr Eye Res 41, 1092–1097.CrossRefGoogle Scholar
  55. Zhou, Y., Xiao, C., and Pu, M. (2017). High glucose levels impact visual response properties of retinal ganglion cells in C57 mice—an in vitro physiological study. Sci China Life Sci 60, 1428–1435.CrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Biomedical Engineering, Institute of Natural Sciences and Bio-X InstituteShanghai Jiao Tong UniversityShanghaiChina
  2. 2.Department of Ophthalmology, West China HospitalSichuan UniversityChengduChina

Personalised recommendations