Skip to main content
SpringerLink
Log in

Pathophysiology of ROP

  • Chapter
  • First Online:
Retinopathy of Prematurity

  • 1167 Accesses

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 54.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 69.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. 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.

    Article  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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.

    PubMed  Google Scholar 

  4. 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.

    CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity. N Engl J Med. 2012;367(26):2515–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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.

    Article  CAS  PubMed  Google Scholar 

  12. Schepens CL. A new ophthalmoscope demonstration. Trans Am Acad Ophthalmol Otolaryngol. 1947;51:298–301.

    CAS  PubMed  Google Scholar 

  13. Hartnett ME. Ophthalmology. 2015 Jan;122(1):200-10.

    Google Scholar 

  14. Patz A. Studies on retinal neovascularization. Friedenwald lecture. Invest Ophthalmol Vis Sci. 1980;19(10):1133–8.

    CAS  PubMed  Google Scholar 

  15. 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.

    Article  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. Cunningham S, Fleck BW, Elton RA, Mclntosh N. Transcutaneous oxygen levels in retinopathy of prematurity. Lancet. 1995;346:1464–5.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 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.

    CAS  PubMed  Google Scholar 

  20. 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.

    Article  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    CAS  PubMed  Google Scholar 

  23. 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.

    Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    CAS  Google Scholar 

  26. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 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.

    Google Scholar 

  28. 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.

    Article  Google Scholar 

  29. 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.

    Article  Google Scholar 

  30. 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.

    Article  Google Scholar 

  31. 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.

    Article  PubMed  Google Scholar 

  32. 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).

    Google Scholar 

  33. Hellström A, Smith LEH, Dammann O. Retinopathy of prematurity. Lancet. 2013;382(9902):1445–57.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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.

    Google Scholar 

  38. 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.

    Google Scholar 

  39. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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.

    CAS  PubMed  Google Scholar 

  42. 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.

    CAS  PubMed  Google Scholar 

  43. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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.

    CAS  PubMed  Google Scholar 

  46. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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.

    Google Scholar 

  48. 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.

    CAS  Google Scholar 

  49. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  51. 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.

    Google Scholar 

  52. 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.

    PubMed  PubMed Central  Google Scholar 

  53. Ward JPT. Oxygen sensors in context. Biochimica et Biophysica Acta (BBA)—Bioenergetics. 2008;1777(1):1–14.

    Google Scholar 

  54. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Saugstad OD. Oxidative stress in the newborn—a 30-year perspective. Biol Neonate. 2005;88(3):228–36.

    Google Scholar 

  56. 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.

    Article  PubMed  Google Scholar 

  57. 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.

    Article  CAS  PubMed  Google Scholar 

  58. Barnett JM, McCollum GW, Penn JS. Role of cytosolic phospholipase A2 in retinal neovascularization. Invest Ophthalmol Vis Sci. 2010;51(2):1136–42.

    Article  PubMed  PubMed Central  Google Scholar 

  59. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Rey S, Semenza GL. Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res. 2010.

    Google Scholar 

  61. 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.

    Article  PubMed  Google Scholar 

  62. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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.

    Article  CAS  PubMed  Google Scholar 

  64. 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.

    Article  CAS  Google Scholar 

  65. 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.

    Article  CAS  PubMed  Google Scholar 

  66. 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.

  67. 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.

  68. 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.

    Article  Google Scholar 

  69. 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.

    Google Scholar 

  70. Hoppe G, et al. Proc Natl Acad Sci U S A. 2016 May 3;113(18):E2516–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  72. 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.

    Article  CAS  PubMed  Google Scholar 

  73. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Ophthalmology and Visual Sciences, University of Utah/John A. Moran Eye Center, 65 Mario Capecchi Dr, Salt Lake City, UT, 84132, USA

    Mary Elizabeth Hartnett

Authors
  1. Mary Elizabeth Hartnett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mary Elizabeth Hartnett .

Editor information

Editors and Affiliations

  1. KYDOFT, Santiago, Chile

    Andrés Kychenthal B.

  2. KYDOFT, Santiago, Chile

    Paola Dorta S.

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

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

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-52190-9_1

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-52188-6

  • Online ISBN: 978-3-319-52190-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation