Abstract
We attempted to explore a noninvasive, easily applicable and economically affordable therapy for retinopathy of prematurity (ROP). Rat pups were raised in 80% oxygen from postnatal day 7 to P12, and returned to room air. Travoprost eye drops were administered twice a day for 7 days, to reduce intraocular pressure (IOP) by about 20%. Immunohistochemical staining was performed to visualize vessel endothelial cells, to analyze retinal neurons and cytoarchitecture. Behavioral experiments were carried out to test visual acuity and contrast sensitivity. At the end of the 7-day treatment, the number of vessels extending to the vitreous body was significantly reduced and retinal vessel density increased. This improvement was maintained to the end of the 12th week. In the central retina of the model group, the horizontal cells were completely wiped out, the outer plexiform layer was undetectable, and the rod bipolar cell dendrites sprouted into the outer nuclear layer. The treatment partially reverted these architectural changes. Most importantly, behavioral experiments revealed significantly improved visual acuity and contrast sensitivity in the treated group. Therefore, reducing IOP could potentially serve as a safe and economical measure to treat ROP.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Asano, M.K., and Dray, P.B. (2014). Retinopathy of prematurity. Dis Mon 60, 282–291.
Ashton, N. (1954). Pathological basis of retrolental fibroplasia. Br J Ophthalmol 38, 385–396.
Ashton, N., Ward, B., Serpell, G. (1953). Role of oxygen in the genesis of retrolental fibroplasia.; Ashton, N., Ward, B., and Serpell, G. ((1953))). Role of oxygen in the genesis of retrolental fibroplasia: a preliminary report. Br J Ophthalmol 37, 513–520.
Campbell, K. (1951). Intensive oxygen therapy as a possible cause of retrolental fibroplasia; a clinical approach. Med J Aust 2, 48.
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. Graefes Arch Clin Exp Ophthalmol 245, 1727–1730.
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.
Early Treatment for Retinopathy of Prematurity Cooperative Group. (2003). Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol (Chicago, Ill: 1960) 121, 1684.
Elsas, F., Botsford, J., Braune, K., Cassady, G., Jones, J., Kimble, J., Kline, L., Lampton, G., Witherspoon, D., and Young, M. (1988). Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Pediatrics 81, 697–706.
Elsas, F, Collins, M, Jones, J, Kimble, J, Kline, L, Witherspoon, D, Roth, A, Demorest, B, Gilbert, W, and Plotsky, D (2001). Multicenter trial of cryotherapy for retinopathy of prematurity. Arch Ophthalmol 119, 1110–1118.
Euler, T., and Wässle, H. (1995). Immunocytochemical identification of cone bipolar cells in the rat retina. J Comp Neurol 361, 461–478.
Friedenwald, J.S., Owens, W.C., and Owens, E.U. (1951). Retrolental fibroplasia in premature infants. III. The pathology of the disease. Trans Am Soc Ophthalmol Otolaryngol Allergy 49, 207–234.
Ghosh, K.K., Bujan, S., Haverkamp, S., Feigenspan, A., and Wässle, H. (2004). Types of bipolar cells in the mouse retina. J Comp Neurol 469, 70–82.
Goldenberg, R.L., Culhane, J.F., Iams, J.D., and Romero, R. (2008). Epidemiology and causes of preterm birth. Lancet 371, 75–84.
Kolb, H. (1974). The connections between horizontal cells and photoreceptors in the retina of the cat: electron microscopy of Golgi preparations. J Comp Neurol 155, 1–14.
Krause, A.C. (1946). Congenital encephalo-ophthalmic dysplasia. Arch Ophthalmol 36, 387–444.
Lange, C., Ehlken, C., Stahl, A., Martin, G., Hansen, L., and Agostini, H.T. (2009). Kinetics of retinal vaso-obliteration and neovascularisation in the oxygen-induced retinopathy (OIR) mouse model. Graefes Arch Clin Exp Ophthalmol 247, 1205–1211.
Liu, L., Li, X., Killer, H.E., Cao, K., Li, J., and Wang, N. (2019). Changes in retinal and choroidal morphology after cerebrospinal fluid pressure reduction: a Beijing iCOP study. Sci China Life Sci 62, 268–271.
Lorenz, B., Spasovska, K., Elflein, H., and Schneider, N. (2009). Wide-field digital imaging based telemedicine for screening for acute retinopathy of prematurity (ROP). Six-year results of a multicentre field study. Graefes Arch Clin Exp Ophthalmol 247, 1251–1262.
McGill, T.J., Douglas, R.M., Lund, R.D., and Prusky, G.T. (2004). Quantification of spatial vision in the Royal College of Surgeons rat. Invest Ophthalmol Vis Sci 45, 932–936.
McNamara, J.A., Tasman, W., Brown, G.C., and Federman, J.L. (1991). Laser photocoagulation for stage 3+ retinopathy of prematurity. Ophthalmology 98, 576–580.
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.
Moskowitz, A., Hansen, R., and Fulton, A. (2005). Early ametropia and rod photoreceptor function in retinopathy of prematurity. Optom Vis Sci 82, 307–317.
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. Br J Ophthalmol 88, 1149–1153.
Patz, A. (1954). Oxygen studies in retrolental fibroplasia. IV. Clinical and experimental observations. Am J Ophthalmol 38, 291–308.
Patz, A. (1982). Clinical and experimental studies on retinal neovascularization. Am J Ophthalmol 94, 715–743.
Patz, A., Eastham, A., Higginbotham, D.H., and Kleh, T. (1953). Oxygen studies in retrolental fibroplasia. II. The production of the microscopic changes of retrolental fibroplasia in experimental animals. Am J Ophthalmol 36, 1511–1522.
Patz, A., Hoeck, L.E., and De La Cruz, E. (1952). Studies on the effect of high oxygen administration in retrolental fibroplasia. I. Nursery observations. Am J Ophthalmol 35, 1248–1253.
Peichl, L., and Gonzalez-Soriano, J. (1993). Unexpected presence of neurofilaments in axon-bearing horizontal cells of the mammalian retina. J Neurosci 13, 4091–4100.
Penn, J.S., Tolman, B.L., and Lowery, L.A. (1993). Variable oxygen exposure causes preretinal neovascularization in the newborn rat. Invest Ophthalmol Vis Sci 34, 576–585.
Prusky, G.T., West, P.W.R., and Douglas, R.M. (2000). Behavioral assessment of visual acuity in mice and rats. Vis Res 40, 2201–2209.
Qiao, L., Zhang, X., Jan, C., Li, X., Li, M., and Wang, H. (2019). Macular retinal thickness and flow density change by optical coherence tomography angiography after posterior scleral reinforcement. Sci China Life Sci 62, 930–936.
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.
Ricci, B. (1990). Oxygen-induced retinopathy in the rat model. Doc Ophthalmol 74, 171–177.
Ricci, B., Calogero, G., Caprilli, A., and Quaranta-Leoni, F.M. (1991). Reduced severity of oxygen-induced retinopathy in the newborn rat after topical administration of timolol maleate. Doc Ophthalmol 77, 47–56.
Sandman, D., Boycott, B.B., and Peichl, L. (1996). The horizontal cells of artiodactyl retinae: a comparison with Cajal’s descriptions. Vis Neurosci 13, 735–746.
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.
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.
Smith, L.E.H. (2003). Pathogenesis of retinopathy of prematurity. Semin Neonatol 8, 469–473.
Smith, L.E., Wesolowski, E., Mclellan, A., Kostyk, S.K., D’amato, R., Sullivan, R., and D’amore, P.A. (1994). Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 35, 101–111.
Stahl, A., Krohne, T.U., Eter, N., Oberacher-Velten, I., Guthoff, R., Meltendorf, S., Ehrt, O., Aisenbrey, S., Roider, J., Gerding, H., et al. (2018). Comparing alternative ranibizumab dosages for safety and efficacy in retinopathy of prematurity. JAMA Pediatr 172, 278–286.
Suzuki, H., and Pinto, L. (1986). Response properties of horizontal cells in the isolated retina of wild- type and pearl mutant mice. J Neurosci 6, 1122–1128.
Szél, Á., and Röhlich, P. (1992). Two cone types of rat retina detected by anti-visual pigment antibodies. Exp Eye Res 55, 47–52.
Wang, X., Shen, K., Lu, F., and He, S. (2019). Long-lasting impairments in rodent oxygen-induced retinopathy measured by retinal vessel density and visual function. Sci China Life Sci 62, 681–690.
Xin, C., Tian, N., Li, M., Wang, H., and Wang, N. (2018). Mechanism of the reconstruction of aqueous outflow drainage. Sci China Life Sci 61, 534–540.
Zhang, J., Jia, H., Wang, J., Xiong, Y., Li, J., Li, X., Zhao, J., Zhang, X., You, Q., Zhu, G., et al. (2019). A novel deletion mutation, c.1296delT in the BCOR gene, is associated with oculo-facio-cardio-dental syndrome. Sci China Life Sci 62, 119–125.
Zhang, X., Yuan, Q., and Gao, X. (2018). Assessment of the MT1-MMP expression level of different cell lines by the naked eye. Sci China Life Sci 61, 492–500.
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.
Acknowledgements
We thank Ms. Jiaying Ju for technical support. This work was funded by a key project of the National Natural Science Foundation of China (31030036) to SH.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The author(s) declare that they have no conflict of interest. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest, or non-financial interest in the subject matter or materials discussed in this manuscript. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
Supporting Information
Rights and permissions
About this article
Cite this article
Du, R., Wang, X., Shen, K. et al. Decreasing intraocular pressure significantly improves retinal vessel density, cytoarchitecture and visual function in rodent oxygen induced retinopathy. Sci. China Life Sci. 63, 290–300 (2020). https://doi.org/10.1007/s11427-018-9559-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-018-9559-x