Abstract
It is difficult to study mechanisms involved in normal or pathologic human retinal vascular development because vascularization occurs before term birth. It is impossible to ethically study the mechanisms in human infants and observational analyses of infant eyes are also difficult since the growth of retinal vessels occurs before term birth in the human. However, studies in animals that vascularize their retinas after birth provide opportunities to learn about the effects of various stressors that premature human infants experience on the ongoing vascuarlization of retina. Nonetheless, species differences must be accounted for. This chapter will review pathophysiology in ROP based on careful analyses that account for different cell type interactions in the retina on physiologic or pathologic angiogenesis. However, most studies are in non-human species because it is in part difficult to obtain quality human fetal tissue.
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Chan-Ling T, McLeod DS, Hughes S, Baxter L, Chu Y, Hasegawa T, et al. Astrocyte-endothelial cell relationships during human retinal vascular development. Invest Ophthalmol Vis Sci. 2004;45(6):2020–32.
McLeod DS, Hasegawa T, Prow T, Merges C, Lutty G. The initial fetal human retinal vasculature develops by vasculogenesis. Dev Dyn. 2006;235(12):3336–47. doi:10.1002/dvdy.20988.
Dorrell MI, Aguilar E, Friedlander M. Retinal vascular development is mediated by endothelial filopodia, a preexisting astrocytic template and specific R-cadherin adhesion. Invest Ophthalmol Vis Sci. 2002;43(11):3500–10.
Chan-Ling T, Gock B, Stone J. The effect of oxygen on vasoformative cell division: evidence that ‘physiological hypoxia’ is the stimulus for normal retinal vasculogenesis. Invest Ophthalmol Vis Sci. 1995;36:1201–14.
Bai Y, J-X Ma, Guo J, Wang J, Zhu M, Chen Y, et al. Müller cell-derived VEGF is a significant contributor to retinal neovascularization. J Pathol. 2009;219(4):446–54.
Jiang Y, Wang H, Culp D, Yang Z, Fotheringham L, Flannery J, et al. Targeting Muller cell-derived VEGF164 to reduce intravitreal neovascularization in the rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2014;55(2):824–31. doi:10.1167/iovs.13-13755.
Sapieha P, Sirinyan M, Hamel D, Zaniolo K, Joyal JS, Cho JH, et al. The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat Med. 2008;14(10):1067–76.
Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity. N Engl J Med. 2012;367(26):2515–26.
Saugstad OD, Ramji S, Soll RF, Vento M. Resuscitation of newborn infants with 21% or 100% oxygen: an updated systematic review and meta-analysis. Neonatology. 2008;94(3):176–82. doi:10.1159/000143397.
Ashton N, Ward B, Serpell G. Effect of oxygen on developing retinal vessels with particular reference to the problem of retrolental fibroplasia. Br J Ophthalmol. 1954;38:397–430.
Patz A, Hoeck LE, De La Cruz E. Studies on the effect of high oxygen administration in retrolental fibroplasia. I. Nursery observations. Am J Ophthalmol. 1952;35(9):1248–53.
Schepens CL. A new ophthalmoscope demonstration. Trans Am Acad Ophthalmol Otolaryngol. 1947;51:298–301.
Hartnett ME. Ophthalmology. 2015 Jan;122(1):200-10.
Patz A. Studies on retinal neovascularization. Friedenwald lecture. Invest Ophthalmol Vis Sci. 1980;19(10):1133–8.
Shah PK, Narendran V, Kalpana N. Aggressive posterior retinopathy of prematurity in large preterm babies in South India. Arch Dis Child Fetal Neonatal Ed. 2012;97(5):F371–5. doi:10.1136/fetalneonatal-2011-301121.
Yamada H, Yamada E, Hackett SF, Ozaki H, Okamoto N, Campochiaro PA. Hyperoxia causes decreased expression of vascular endothelial growth factor and endothelial cell apoptosis in adult retina. J Cell Physiol. 1999;179(2):149–56. doi:10.1002/(sici)1097-4652(199905)179:2<149:aid-jcp5>3.0.co;2-2.
Cunningham S, Fleck BW, Elton RA, Mclntosh N. Transcutaneous oxygen levels in retinopathy of prematurity. Lancet. 1995;346:1464–5.
Di Fiore JM, Kaffashi F, Loparo K, Sattar A, Schluchter M, Foglyano R, et al. The relationship between patterns of intermittent hypoxia and retinopathy of prematurity in preterm infants. Pediatr Res. 2012;72(6):606–12. doi:10.1038/pr.2012.132.
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;42:222–8.
Buhimschi IA, Buhimschi CS, Pupkin M, Weiner CP. Beneficial impact of term labor: Nonenzymatic antioxidant reserve in the human fetus. Am J Obstet Gynecol. 2003;189(1):181–8.
Sanchez-Alvarez ROSA, Almeida A, Medina JM. Oxidative stress in preterm rat brain is due to mitochondrial dysfunction. Pediatr Res. 2002;51(1):34–9.
Najarian T, Hardy P, Hou X, Lachapelle J, Doke A, Gobeil F Jr, et al. Preservation of neural function in the perinate by high PGE2 levels acting via EP2 receptors. J Appl Physiol. 2000;89(2):777–84.
Wang H, Yang Z, Jiang Y, Hartnett ME. Endothelial NADPH oxidase 4 mediates vascular endothelial growth factor receptor 2-induced intravitreal neovascularization in a rat model of retinopathy of prematurity. Mol Vis. 2014;20:231–41.
Niesman MR, Johnson KA, Penn JS. Therapeutic effect of liposomal superoxide dismutase in an animal model of retinopathy of prematurity. Neurochem Res. 1997;22(5):597–605.
McColm JR, Geisen P, Hartnett ME. VEGF isoforms and their expression after a single episode of hypoxia or repeated fluctuations between hyperoxia and hypoxia: relevance to clinical ROP. Mol Vision. 2004;10:512–20.
Byfield G, Budd S, Hartnett ME. The role of supplemental oxygen and JAK/STAT signaling in intravitreous neovascularization in a ROP rat model. Invest Ophthalmol Vis Sci. 2009;50(7):3360–5. doi:10.1167/iovs.08-3256.
Group TS-RMS. Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics. 2000;105(2):295–310.
Hartnett ME, Lane RH. Effects of oxygen on the development and severity of retinopathy of prematurity. J AAPOS Official Publ Am Assoc Pediatr Ophthalmol Strabismus/Am Assoc Pediatr Ophthalmol Strabismus. 2013;17(3):229–34. doi:10.1016/j.jaapos.2012.12.155.
Vanderveen DK, Mansfield TA, Eichenwald EC. Lower oxygen saturation alarm limits decrease the severity of retinopathy of prematurity. J Am Assoc Pediatr Ophthalmol Strabismus. 2006;10(5):445–8.
Wallace DK, Veness-Meehan KA, Miller WC. Incidence of severe retinopathy of prematurity before and after a modest reduction in target oxygen saturation levels. J Am Assoc Pediatr Ophthalmol Strabismus. 2007;11(2):170–4.
Sears JE, Pietz J, Sonnie C, Dolcini D, Hoppe G. A change in oxygen supplementation can decrease the incidence of retinopathy of prematurity. Ophthalmology. 2009;116(3):513–8.
Gaynon MW. Rethinking stop-rop: is it worthwhile trying to modulate excessive VEGF levels in prethreshold rop eyes by systemic intervention?: A review of the role of oxygen, light adaptation state, and anemia in prethreshold ROP. Retina. 2006;26(7).
Hellström A, Smith LEH, Dammann O. Retinopathy of prematurity. Lancet. 2013;382(9902):1445–57.
Lofqvist C, Chen J, Connor KM, Smith ACH, Aderman CM, Liu N, et al. From the cover: IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth. Proc Natl Acad Sci. 2007;104(25):10589–94.
Chang KH, Chan-Ling T, McFarland EL, Afzal A, Pan H, Baxter LC, et al. IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development. Proc Natl Acad Sci. 2007;104(25):10595–600.
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):868–73.
Tolman BL, Henry MM, Lowery LA, Penn JS. Oxygen-induced retinopathy in the rat: the period of variable oxygen cycles effects the severity of the pathology. Invest Ophthalmol Vis Sci. 1993;34(Suppl):838.
Wang H, Smith GW, Yang Z, Jiang Y, McCloskey M, Greenberg K, et al. Short hairpin RNA-mediated knockdown of VEGFA in Muller cells reduces intravitreal neovascularization in a rat model of retinopathy of prematurity. Am J Pathol. 2013;. doi:10.1016/j.ajpath.2013.05.011.
Wang H, Yang Z, Jiang Y, Flannery J, Hammond S, Kafri T, et al. Quantitative analyses of retinal vascular area and density after different methods to reduce VEGF in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2014;55(2):737–44. doi:10.1167/iovs.13-13429.
Yang Z, Wang H, Jiang Y, Hartnett ME. VEGFA activates erythropoietin receptor and enhances VEGFR2-mediated pathological angiogenesis. Am J Pathol. 2014;184(4):1230–9. doi:10.1016/j.ajpath.2013.12.023.
Smith LEH, 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):101–11.
McLeod DS, Crone SN, Lutty GA. Vasoproliferation in the neonatal dog model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci. 1996;37(7):1322–33.
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(7):4039–47.
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):1163–77.
Stone J, Itin A, Alon T, Peer J, Gnessin H, Chan-Ling T, et al. Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J Neurosci. 1995;15:4738–47.
Stalmans I, Ng YS, Rohan R, Fruttiger M, Bouche A, Yuce A, et al. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest. 2002;109(3):327–36.
Lundkvist A, Lee S, Iruela-Arispe L, Betsholtz C, Gerhardt H. Growth factor gradients in vascular patterning. Novartis Found Symp. 2007;283:194–201; discussion-6, 38–41.
Geisen P, Peterson L, Martiniuk D, Uppal A, Saito Y, Hartnett M. Neutralizing antibody to VEGF reduces intravitreous neovascularization and does not interfere with vascularization of avascular retina in an ROP model. Mol Vision. 2008;14:345–57.
Zeng G, Taylor SM, McColm JR, Kappas NC, Kearney JB, Williams LH, et al. Orientation of endothelial cell division is regulated by VEGF signaling during blood vessel formation. Blood. 2007;109(4):1345–52.
Bell EF, Strauss RG, Widness JA, Mahoney LT, Mock DM, Seward VJ, et al. Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants. Pediatrics. 2005;115(6):1685–91.
Kirpalani H, Whyte RK, Andersen C, Asztalos EV, Heddle N, Blajchman MA et al. The premature infants in need of transfusion (pint) study: a randomized, controlled trial of a restrictive (LOW) versus liberal (HIGH) transfusion threshold for extremely low birth weight infants. J Pediatr. 2006;149(3):301–7.
Ohls RK, Christensen RD, Kamath-Rayne BD, Rosenberg A, Wiedmeier SE, Roohi M, et al. A randomized, masked, placebo-controlled study of darbepoetin Alfa in preterm infants. Pediatrics. 2013. doi:10.1542/peds.2013-0143.
Ward JPT. Oxygen sensors in context. Biochimica et Biophysica Acta (BBA)—Bioenergetics. 2008;1777(1):1–14.
Wang H, Zhang SX, Hartnett ME. Signaling pathways triggered by oxidative stress that mediate features of severe retinopathy of prematurity. JAMA Ophthalmol. 2013;131(1):80–5. doi:10.1001/jamaophthalmol.2013.986.
Saugstad OD. Oxidative stress in the newborn—a 30-year perspective. Biol Neonate. 2005;88(3):228–36.
Kermorvant-Duchemin E, Sapieha P, Sirinyan M, Beauchamp M, Checchin D, Hardy P, et al. Understanding ischemic retinopathies: emerging concepts from oxygen-induced retinopathy. Doc Ophthalmol. 2010;120(1):51–60.
Dammann O, Phillips TM, Allred EN, O’Shea TM, Paneth N, Van Marter LJ, et al. Mediators of fetal inflammation in extremely low gestational age newborns. Cytokine. 2001;13(4):234–9.
Barnett JM, McCollum GW, Penn JS. Role of cytosolic phospholipase A2 in retinal neovascularization. Invest Ophthalmol Vis Sci. 2010;51(2):1136–42.
Yanni SE, Barnett JM, Clark ML, Penn JS. The role of PGE2 receptor EP4 in pathologic ocular angiogenesis. Invest Ophthalmol Vis Sci. 2009;50(11):5479–86.
Rey S, Semenza GL. Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res. 2010.
Brafman A, Mett I, Shafir M, Gottlieb H, Damari G, Gozlan-Kelner S, et al. Inhibition of oxygen-induced retinopathy in RTP801-deficient mice. Invest Ophthalmol Vis Sci. 2004;45(10):3796–805.
Tang Y, Scheef EA, Wang S, Sorenson CM, Marcus CB, Jefcoate CR, et al. CYP1B1 expression promotes the proangiogenic phenotype of endothelium through decreased intracellular oxidative stress and thrombospondin-2 expression. Blood. 2009;113(3):744–54.
Caro AA, Cederbaum AI. Role of cytochrome P450 in phospholipase A2- and arachidonic acid-mediated cytotoxicity. Free Radic Biol Med. 2006;40(3):364–75.
Hardy P, Beauchamp M, Sennlaub F, Gobeil J, Tremblay L, Mwaikambo B, et al. New insights into the retinal circulation: inflammatory lipid mediators in ischemic retinopathy. Prostaglandins Leukot Essent Fat Acids. 2005;72(5):301–25.
Beauchamp MH, Sennlaub F, Speranza G, Gobeil J, 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):1885–94.
Soghier LM, Brion LP. Cysteine, cystine or N-acetylcysteine supplementation in parenterally fed neonates. Cochrane Database Syst Rev. 2006(4):CD004869. doi:10.1002/14651858.CD004869.pub2.
Brion LP, Bell EF, Raghuveer TS. Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2003(4):CD003665. doi:10.1002/14651858.cd003665.
Dani C, Lori I, Favelli F, Frosini S, Messner H, Wanker P, et al. Lutein and zeaxanthin supplementation in preterm infants to prevent retinopathy of prematurity: a randomized controlled study. J Maternal-Fetal Neonatal Med. 2011;25(5):523–7.
Al Shabrawey M, Bartoli M, El Remessy AB, Ma G, Matragoon S, Lemtalsi T et al. Role of NADPH oxidase and Stat3 in statin-mediated protection against diabetic retinopathy. Invest Ophthalmol Vis Sci. 2008;49(7):3231–8.
Hoppe G, et al. Proc Natl Acad Sci U S A. 2016 May 3;113(18):E2516–25.
McCloskey M, Wang H, Jiang Y, Smith GW, Strange J, Hartnett ME. Anti-VEGF antibody leads to later atypical intravitreous neovascularization and activation of angiogenic pathways in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2013;54(3):2020–6. doi:10.1167/iovs.13-11625.
Reynolds JD, Hardy RJ, Kennedy KA, Spencer R, van Heuven WAJ, Fielder AR. Lack of efficacy of light reduction in preventing retinopathy of prematurity. N Engl J Med. 1998;338:1572–6.
Rao S, Chun C, Fan J, Kofron JM, Yang MB, Hegde RS, et al. A direct and melanopsin-dependent fetal light response regulates mouse eye development. Nature. 2013;494(7436):243–6. doi:10.1038/nature11823.
Yang MB, Rao S, Copenhagen DR, Lang RA. Length of day during early gestation as a predictor of risk for severe retinopathy of prematurity. Ophthalmology. 2013;120(12):2706–13. doi:10.1016/j.ophtha.2013.07.051.
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Hartnett, M.E. (2017). Pathophysiology of ROP. In: Kychenthal B., A., Dorta S., P. (eds) Retinopathy of Prematurity. Springer, Cham. https://doi.org/10.1007/978-3-319-52190-9_1
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