Abstract
Ischaemic vascular disease in the retina may either leave retina permanently ischaemic with slow degradation of vision, or alternatively lead to proliferative vascular disease, which can also destroy vision. To investigate the molecular and cellular mechanisms that contribute to this pathology a mouse model has been studied extensively. The model is based on the exposure of mouse pups to hyperoxia during a phase when their retinal vasculature is still developing. This leads to capillary depletion, and upon return to room air, results in retinal ischaemia and proliferative vascular disease in the retinal vasculature (oxygen-induced retinopathy (OIR)). Numerous studies using this OIR model have revealed that the regulation of angiogenic factors and the influence of inflammatory cells play a pivotal role in the vascular pathogenesis. It has also been demonstrated in the OIR model that proliferative vascular disease is not the only possible outcome of ischaemia-induced angiogenesis in the retina, but that ischaemic areas in the retina can be revascularised with healthy blood vessels. Therefore, understanding the factors that control the balance between pathological and healthy angiogenesis in the OIR model may have important implications for human retinal ischaemic disease.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
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 (1): 101–111.
Zhang S, Leske DA, Holmes JM . Neovascularization grading methods in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 2000; 41 (3): 887–891.
Kremer I, Kissun R, Nissenkorn I, Ben-Sira I, Garner A . Oxygen-induced retinopathy in newborn kittens. A model for ischemic vasoproliferative retinopathy. Invest Ophthalmol Vis Sci 1987; 28 (1): 126–130.
Ricci B . Oxygen-induced retinopathy in the rat model. Doc Ophthalmol 1990; 74 (3): 171–177.
McLeod DS, Brownstein R, Lutty GA . Vaso-obliteration in the canine model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 1996; 37 (2): 300–311.
Cao R, Jensen LD, Soll I, Hauptmann G, Cao Y . Hypoxia-induced retinal angiogenesis in zebrafish as a model to study retinopathy. PLoS One 2008; 3 (7): e2748.
Connor KM, Krah NM, Dennison RJ, Aderman CM, Chen J, Guerin KI et al. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat Protoc 2009; 4 (11): 1565–1573.
Aguilar E, Dorrell MI, Friedlander D, Jacobson RA, Johnson A, Marchetti V et al. Chapter 6. Ocular models of angiogenesis. Methods Enzymol 2008; 444: 115–158.
Fruttiger M . Development of the retinal vasculature. Angiogenesis 2007; 10 (2): 77–88.
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 (9): 1205–1211.
Claxton S, Fruttiger M . Role of arteries in oxygen induced vaso-obliteration. Exp Eye Res 2003; 77 (3): 305–311.
Beauchamp MH, Sennlaub F, Speranza G, Gobeil Jr F, Checchin D, Kermorvant-Duchemin E et al. Redox-dependent effects of nitric oxide on microvascular integrity in oxygen-induced retinopathy. Free Radic Biol Med 2004; 37 (11): 1885–1894.
Gu X, El Remessy AB, Brooks SE, Al Shabrawey M, Tsai NT, Caldwell RB . Hyperoxia induces retinal vascular endothelial cell apoptosis through formation of peroxynitrite. Am J Physiol Cell Physiol 2003; 285 (3): C546–C554.
Gu X, Samuel S, El Shabrawey M, Caldwell RB, Bartoli M, Marcus DM et al. Effects of sustained hyperoxia on revascularization in experimental retinopathy of prematurity. Invest Ophthalmol Vis Sci 2002; 43 (2): 496–502.
Shweiki D, Itin A, Soffer D, Keshet E . Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992; 359 (6398): 843–845.
Alon T, Hemo I, Itin A, Pe’er J, Stone J, Keshet E . Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1995; 1 (10): 1024–1028.
Benjamin LE, Hemo I, Keshet E . A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF- B and VEGF. Development 1998; 125 (9): 1591–1598.
Koch CJ . Measurement of absolute oxygen levels in cells and tissues using oxygen sensors and 2-nitroimidazole EF5. Methods Enzymol 2002; 352: 3–31.
Ozaki H, Seo MS, Ozaki K, Yamada H, Yamada E, Okamoto N et al. Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization. Am J Pathol 2000; 156 (2): 697–707.
Agostini H, Boden K, Unsold A, Martin G, Hansen L, Fiedler U et al. A single local injection of recombinant VEGF receptor 2 but not of Tie2 inhibits retinal neovascularization in the mouse. Curr Eye Res 2005; 30 (4): 249–257.
Sone H, Kawakami Y, Segawa T, Okuda Y, Sekine Y, Honmura S et al. Effects of intraocular or systemic administration of neutralizing antibody against vascular endothelial growth factor on the murine experimental model of retinopathy. Life Sci 1999; 65 (24): 2573–2580.
Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 2003; 161 (6): 1163–1177.
Hellstrom A, Perruzzi C, Ju M, Engstrom E, Hard AL, Liu JL et al. Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity. Proc Natl Acad Sci USA 2001; 98 (10): 5804–5808.
Kondo T, Vicent D, Suzuma K, Yanagisawa M, King GL, Holzenberger M et al. Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization. J Clin Invest 2003; 111 (12): 1835–1842.
Lofqvist C, Chen J, Connor KM, Smith AC, Aderman CM, Liu N et al. IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth. Proc Natl Acad Sci USA 2007; 104 (25): 10589–10594.
Chen J, Connor KM, Aderman CM, Smith LE . Erythropoietin deficiency decreases vascular stability in mice. J Clin Invest 2008; 118 (2): 526–533.
Hackett SF, Wiegand S, Yancopoulos G, Campochiaro PA . Angiopoietin-2 plays an important role in retinal angiogenesis. J Cell Physiol 2002; 192 (2): 182–187.
Dorrell MI, Aguilar E, Jacobson R, Trauger SA, Friedlander J, Siuzdak G et al. Maintaining retinal astrocytes normalizes revascularization and prevents vascular pathology associated with oxygen-induced retinopathy. Glia 2009; 58 (1): 43–54.
Downie LE, Pianta MJ, Vingrys AJ, Wilkinson-Berka JL, Fletcher EL . AT1 receptor inhibition prevents astrocyte degeneration and restores vascular growth in oxygen-induced retinopathy. Glia 2008; 56 (10): 1076–1090.
Ishida S, Usui T, Yamashiro K, Kaji Y, Amano S, Ogura Y et al. VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med 2003; 198 (3): 483–489.
Ilg RC, Davies MH, Powers MR . Altered retinal neovascularization in TNF receptor-deficient mice. Curr Eye Res 2005; 30 (11): 1003–1013.
Rotschild T, Nandgaonkar BN, Yu K, Higgins RD . Dexamethasone reduces oxygen induced retinopathy in a mouse model. Pediatr Res 1999; 46 (1): 94–100.
Sharma J, Barr SM, Geng Y, Yun Y, Higgins RD . Ibuprofen improves oxygen-induced retinopathy in a mouse model. Curr Eye Res 2003; 27 (5): 309–314.
Yoshida S, Yoshida A, Ishibashi T, Elner SG, Elner VM . Role of MCP-1 and MIP-1alpha in retinal neovascularization during postischemic inflammation in a mouse model of retinal neovascularization. J Leukoc Biol 2003; 73 (1): 137–144.
Connor KM, SanGiovanni JP, Lofqvist C, Aderman CM, Chen J, Higuchi A et al. Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med 2007; 13 (7): 868–873.
Dong A, Xie B, Shen J, Yoshida T, Yokoi K, Hackett SF et al. Oxidative stress promotes ocular neovascularization. J Cell Physiol 2009; 219 (3): 544–552.
Brooks SE, Gu X, Samuel S, Marcus DM, Bartoli M, Huang PL et al. Reduced severity of oxygen-induced retinopathy in eNOS-deficient mice. Invest Ophthalmol Vis Sci 2001; 42 (1): 222–228.
Kubota Y, Takubo K, Shimizu T, Ohno H, Kishi K, Shibuya M et al. M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. J Exp Med 2009; 206 (5): 1089–1102.
Checchin D, Sennlaub F, Levavasseur E, Leduc M, Chemtob S . Potential role of microglia in retinal blood vessel formation. Invest Ophthalmol Vis Sci 2006; 47 (8): 3595–3602.
Ritter MR, Banin E, Moreno SK, Aguilar E, Dorrell MI, Friedlander M . Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy. J Clin Invest 2006; 116 (12): 3266–3276.
Dace DS, Khan AA, Kelly J, Apte RS . Interleukin-10 promotes pathological angiogenesis by regulating macrophage response to hypoxia during development. PLoS One 2008; 3 (10): e3381.
Checchin D, Sennlaub F, Levavasseur E, Leduc M, Chemtob S . Potential role of microglia in retinal blood vessel formation. Invest Ophthalmol Vis Sci 2006; 47 (8): 3595–3602.
Rehman J, Li J, Orschell CM, March KL . Peripheral blood ‘endothelial progenitor cells’ are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 2003; 107 (8): 1164–1169.
Timmermans F, Plum J, Yoder MC, Ingram DA, Vandekerckhove B, Case J . Endothelial progenitor cells: identity defined? J Cell Mol Med 2009; 13 (1): 87–102.
Brunner S, Schernthaner GH, Satler M, Elhenicky M, Hoellerl F, Schmid-Kubista KE et al. Correlation of different circulating endothelial progenitor cells to stages of diabetic retinopathy: first in vivo data. Invest Ophthalmol Vis Sci 2009; 50 (1): 392–398.
Caballero S, Sengupta N, Afzal A, Chang KH, Li CS, Guberski DL et al. Ischemic vascular damage can be repaired by healthy, but not diabetic, endothelial progenitor cells. Diabetes 2007; 56 (4): 960–967.
Krenning G, van Luyn MJ, Harmsen MC . Endothelial progenitor cell-based neovascularization: implications for therapy. Trends Mol Med 2009; 15 (4): 180–189.
Natoli R, Provis J, Valter K, Stone J . Gene regulation induced in the C57BL/6J mouse retina by hyperoxia: a temporal microarray study. Mol Vis 2008; 14: 1983–1994.
Recchia FM, Xu L, Penn JS, Boone B, Dexheimer P . Identification of genes and pathways involved in retinal neovascularization by microarray analysis of two animal models of retinal angiogenesis. Invest Ophthalmol Vis Sci 2009, e-pub ahead of print (PMID19834031). doi:10.1167/iovs.09-4006.
Sato T, Kusaka S, Hashida N, Saishin Y, Fujikado T, Tano Y . Comprehensive gene-expression profile in murine oxygen-induced retinopathy. Br J Ophthalmol 2009; 93 (1): 96–103.
Ribatti D, Conconi MT, Nussdorfer GG . Nonclassic endogenous novel [corrected] regulators of angiogenesis. Pharmacol Rev 2007; 59 (2): 185–205.
Zhang SX, Ma JX, Sima J, Chen Y, Hu MS, Ottlecz A et al. Genetic difference in susceptibility to the blood-retina barrier breakdown in diabetes and oxygen-induced retinopathy. Am J Pathol 2005; 166 (1): 313–321.
van Wijngaarden P, Brereton HM, Coster DJ, Williams KA . Genetic influences on susceptibility to oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 2007; 48 (4): 1761–1766.
Yang MB, Donovan EF, Wagge JR . Race, gender, and clinical risk index for babies (CRIB) score as predictors of severe retinopathy of prematurity. J AAPOS 2006; 10 (3): 253–261.
Saunders RA, Donahue ML, Christmann LM, Pakalnis AV, Tung B, Hardy RJ et al. Racial variation in retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol 1997; 115 (5): 604–608.
Ng YK, Fielder AR, Shaw DE, Levene MI . Epidemiology of retinopathy of prematurity. Lancet 1988; 2 (8622): 1235–1238.
Micieli JA, Surkont M, Smith AF . A systematic analysis of the off-label use of bevacizumab for severe retinopathy of prematurity. Am J Ophthalmol 2009; 148 (4): 536–543.
Acknowledgements
AS is supported by a fellowship from Fight for Sight and the Biomedical Research Centre for Ophthalmology and Moorfields Special Trustees, and MF has grant support from the Lowy Medical Research Institute LTD, the Medical Research Council and the Wellcome Trust.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Scott, A., Fruttiger, M. Oxygen-induced retinopathy: a model for vascular pathology in the retina. Eye 24, 416–421 (2010). https://doi.org/10.1038/eye.2009.306
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/eye.2009.306
Keywords
This article is cited by
-
FOXC1 regulates endothelial CD98 (LAT1/4F2hc) expression in retinal angiogenesis and blood-retina barrier formation
Nature Communications (2024)
-
Targeting FSCN1 with an oral small-molecule inhibitor for treating ocular neovascularization
Journal of Translational Medicine (2023)
-
The Warburg effect alters amino acid homeostasis in human retinal endothelial cells: implication for proliferative diabetic retinopathy
Scientific Reports (2023)
-
Transcriptome analysis of AAV-induced retinopathy models expressing human VEGF, TNF-α, and IL-6 in murine eyes
Scientific Reports (2022)
-
Generation and characterization of a Müller-glial-cell-specific Il6ra knockout mouse to delineate the effects of IL-6 trans-signaling in the retina
Scientific Reports (2022)