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Angiogenesis

, Volume 10, Issue 2, pp 133–140 | Cite as

Retinopathy of prematurity

  • Jing Chen
  • Lois E. H. SmithEmail author
Original Paper

Abstract

Retinopathy of prematurity (ROP) is a common blinding disease in children in the developed world despite current treatment, and is becoming increasingly prevalent in the developing world. ROP progresses in two phases. The first phase begins with delayed retinal vascular growth after birth and partial regression of existing vessels, followed by a second phase of hypoxia-induced pathological vessel growth. Two major risk factors of ROP are the use of oxygen and a decreased gestation period. Excessive oxygen contributes to ROP through regulation of vascular endothelial growth factor (VEGF). Suppression of VEGF by oxygen in phase I of ROP inhibits normal vessel growth, whereas elevated levels of VEGF induced by hypoxia in phase II of ROP precipitate pathological vessel proliferation. Insulin-like growth factor 1 (IGF-1) is a critical non-oxygen-regulated factor in ROP. We have found that serum levels of IGF-1 in premature babies directly correlate with the severity of clinical ROP. IGF-1 acts indirectly as a permissive factor by allowing maximal VEGF stimulation of vessel growth. Lack of IGF-1 in preterm infants prevents normal retinal vascular growth in phase I of ROP, despite the presence of VEGF. As infants mature, rising levels of IGF-1 in phase II of ROP allows VEGF stimulated pathological neovascularization. These findings suggest that restoration of IGF-1 to normal levels might be useful in preventing ROP in preterm infants.

Keywords

Hypoxia IGF-1 Neovascularization Prematurity Retinopathy VEGF 

References

  1. 1.
    Silverman W (1980) Retrolental fibroplasia: a modern parable. Grune and Stratton, New YorkGoogle Scholar
  2. 2.
    Terry TL (1944) Retrolental fibroplasia in the premature infant: V. Further studies on fibroplastic overgrowth of the persistent tunica vasculosa lentis. Trans Am Ophthalmol Soc 42:383–396PubMedGoogle Scholar
  3. 3.
    Campbell K (1951) Intensive oxygen therapy as a possible cause of retrolental fibroplasia; a clinical approach. Med J Aust 2:48–50PubMedGoogle Scholar
  4. 4.
    Patz A, Hoeck LE, De La Cruz E (1952) Studies on the effect of high oxygen administration in retrolental fibroplasia. I nursery observations. Am J Ophthalmol 35:1248–1253PubMedGoogle Scholar
  5. 5.
    Ashton N, Ward B, Serpell G (1953) Role of oxygen in the genesis of retrolental fibroplasia; a preliminary report. Br J Ophthalmol 37:513–520PubMedGoogle Scholar
  6. 6.
    Ashton N, Ward B, Serpell G (1954) Effect of oxygen on developing retinal vessels with particular reference to the problem of retrolental fibroplasia. Br J Ophthalmol 38:397–432PubMedGoogle Scholar
  7. 7.
    Kinsey VE, Arnold HJ, Kalina RE, Stern L, Stahlman M, Odell G, Driscoll JM Jr, Elliott JH, Payne J, Patz A (1977) PaO2 levels and retrolental fibroplasia: a report of the cooperative study. Pediatrics 60:655–668PubMedGoogle Scholar
  8. 8.
    Flynn JT (1983) Acute proliferative retrolental fibroplasia: multivariate risk analysis. Trans Am Ophthalmol Soc 81:549–591PubMedGoogle Scholar
  9. 9.
    Johnson L, Quinn GE, Abbasi S, Gerdes J, Bowen FW, Bhutani V (1995) Severe retinopathy of prematurity in infants with birth weights less than 1250 grams: incidence and outcome of treatment with pharmacologic serum levels of vitamin E in addition to cryotherapy from 1985 to 1991. J Pediatr 127:632–639PubMedCrossRefGoogle Scholar
  10. 10.
    Phelps DL, Rosenbaum AL, Isenberg SJ, Leake RD, Dorey FJ (1987) Tocopherol efficacy and safety for preventing retinopathy of prematurity: a randomized, controlled, double-masked trial. Pediatrics 79:489–500PubMedGoogle Scholar
  11. 11.
    Wesolowski E, Smith LE (1994) Effect of light on oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 35:112–119PubMedGoogle Scholar
  12. 12.
    Reynolds JD, Hardy RJ, Kennedy KA, Spencer R, van Heuven WA, Fielder AR (1998) Lack of efficacy of light reduction in preventing retinopathy of prematurity. Light reduction in retinopathy of prematurity (LIGHT-ROP) cooperative group. N Engl J Med 338:1572–1576PubMedCrossRefGoogle Scholar
  13. 13.
    Lutty GA, Chan-Ling T, Phelps DL, Adamis AP, Berns KI, Chan CK, Cole CH, D’Amore PA, Das A, Deng WT, Dobson V, Flynn JT, Friedlander M, Fulton A, Good WV, Grant MB, Hansen R, Hauswirth WW, Hardy RJ, Hinton DR, Hughes S, McLeod DS, Palmer EA, Patz A, Penn JS, Raisler BJ, Repka MX, Saint-Geniez M, Shaw LC, Shima DT, Smith BT, Smith LE, Tahija SG, Tasman W, Trese MT (2006) Proceedings of the third international symposium on retinopathy of prematurity: an update on ROP from the lab to the nursery (November 2003, Anaheim, California). Mol Vis 12:532–580PubMedGoogle Scholar
  14. 14.
    Smith LE (2003) Pathogenesis of retinopathy of prematurity. Semin Neonatol 8:469–473PubMedCrossRefGoogle Scholar
  15. 15.
    Tasman W, Patz A, McNamara JA, Kaiser RS, Trese MT, Smith BT (2006) Retinopathy of prematurity: the life of a lifetime disease. Am J Ophthalmol 141:167–174PubMedCrossRefGoogle Scholar
  16. 16.
    Blanco CL, Baillargeon JG, Morrison RL, Gong AK (2006) Hyperglycemia in extremely low birth weight infants in a predominantly hispanic population and related morbidities. J Perinatol 26:737–741Google Scholar
  17. 17.
    Ertl T, Gyarmati J, Gaal V, Szabo I (2006) Relationship between hyperglycemia and retinopathy of prematurity in very low birth weight infants. Biol Neonate 89:56–59PubMedCrossRefGoogle Scholar
  18. 18.
    Garg R, Agthe AG, Donohue PK, Lehmann CU (2003) Hyperglycemia and retinopathy of prematurity in very low birth weight infants. J Perinatol 23:186–194PubMedCrossRefGoogle Scholar
  19. 19.
    Roth AM (1977) Retinal vascular development in premature infants. Am J Ophthalmol 84:636–640PubMedGoogle Scholar
  20. 20.
    Bell EF, Klein JM (1994) Iowa neonatology handbook: pulmonary comments on oxygen toxicity and retinopathy (ROP) in the premature infant. online: http://www.uihealthcare.com/depts/med/pediatrics/iowaneonatologyhandbook/general/commentsoxygen.html
  21. 21.
    Smith LE, Wesolowski E, McLellan A, Kostyk SK, D’Amato R, Sullivan R, D’Amore PA (1994) Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 35:101–111PubMedGoogle Scholar
  22. 22.
    Flower RW (1990) Perinatal ocular physiology and ROP in the experimental animal model. Doc Ophthalmol 74:153–162PubMedCrossRefGoogle Scholar
  23. 23.
    Penn JS, Tolman BL, Henry MM (1994) Oxygen-induced retinopathy in the rat: relationship of retinal nonperfusion to subsequent neovascularization. Invest Ophthalmol Vis Sci 35:3429–3435PubMedGoogle Scholar
  24. 24.
    Patz A (1982) Clinical and experimental studies on retinal neovascularization. XXXIX Edward Jackson memorial lecture. Am J Ophthalmol 94:715–743PubMedCrossRefGoogle Scholar
  25. 25.
    Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985PubMedCrossRefGoogle Scholar
  26. 26.
    Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309PubMedCrossRefGoogle Scholar
  27. 27.
    Plate KH, Breier G, Weich HA, Risau W (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359:845–848PubMedCrossRefGoogle Scholar
  28. 28.
    Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841–844PubMedCrossRefGoogle Scholar
  29. 29.
    Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845PubMedCrossRefGoogle Scholar
  30. 30.
    Adamis AP, Shima DT, Yeo KT, Yeo TK, Brown LF, Berse B, D’Amore PA, Folkman J (1993) Synthesis and secretion of vascular permeability factor/vascular endothelial growth factor by human retinal pigment epithelial cells. Biochem Biophys Res Commun 193:631–638PubMedCrossRefGoogle Scholar
  31. 31.
    Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487PubMedCrossRefGoogle Scholar
  32. 32.
    Aiello LP, Northrup JM, Keyt BA, Takagi H, Iwamoto MA (1995a) Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 113:1538–1544Google Scholar
  33. 33.
    Chan-Ling T, Gock B, Stone J (1995) The effect of oxygen on vasoformative cell division. Evidence that ‘physiological hypoxia’ is the stimulus for normal retinal vasculogenesis. Invest Ophthalmol Vis Sci 36:1201–1214PubMedGoogle Scholar
  34. 34.
    Dorrell MI, Aguilar E, Friedlander M (2002) Retinal vascular development is mediated by endothelial filopodia, a preexisting astrocytic template and specific R-cadherin adhesion. Invest Ophthalmol Vis Sci 43:3500–3510PubMedGoogle Scholar
  35. 35.
    Stone J, Itin A, Alon T, Pe’er J, Gnessin H, Chan-Ling T, Keshet E (1995) Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J Neurosci 15:4738–4747PubMedGoogle Scholar
  36. 36.
    Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE (1995) Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci USA 92:905–909PubMedCrossRefGoogle Scholar
  37. 37.
    Alon T, Hemo I, Itin A, Pe’er J, Stone J, Keshet E (1995) Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1:1024–1028PubMedCrossRefGoogle Scholar
  38. 38.
    Pierce EA, Foley ED, Smith LE (1996) Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol 114:1219–1228PubMedGoogle Scholar
  39. 39.
    Shih SC, Ju M, Liu N, Smith LE (2003) Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity. J Clin Invest 112:50–57PubMedCrossRefGoogle Scholar
  40. 40.
    Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, Ferrara N, King GL, Smith LE (1995b) Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA 92:10457–10461CrossRefGoogle Scholar
  41. 41.
    Robinson GS, Pierce EA, Rook SL, Foley E, Webb R, Smith LE (1996) Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of proliferative retinopathy. Proc Natl Acad Sci USA 93:4851–4856PubMedCrossRefGoogle Scholar
  42. 42.
    Adamis AP, Shima DT, Tolentino MJ, Gragoudas ES, Ferrara N, Folkman J, D’Amore PA, Miller JW (1996) Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol 114:66–71PubMedGoogle Scholar
  43. 43.
    Donahue ML, Phelps DL, Watkins RH, LoMonaco MB, Horowitz S (1996) Retinal vascular endothelial growth factor (VEGF) mRNA expression is altered in relation to neovascularization in oxygen induced retinopathy. Curr Eye Res 15:175–184PubMedGoogle Scholar
  44. 44.
    Miller JW, Adamis AP, Shima DT, D’Amore PA, Moulton RS, O’Reilly MS, Folkman J, Dvorak HF, Brown LF, Berse B et al (1994) Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol 145:574–584PubMedGoogle Scholar
  45. 45.
    Stone J, Chan-Ling T, Pe’er J, Itin A, Gnessin H, Keshet E (1996) Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity. Invest Ophthalmol Vis Sci 37:290–299PubMedGoogle Scholar
  46. 46.
    Young TL, Anthony DC, Pierce E, Foley E, Smith LE (1997) Histopathology and vascular endothelial growth factor in untreated and diode laser-treated retinopathy of prematurity. J Aapos 1:105–110PubMedCrossRefGoogle Scholar
  47. 47.
    Adamis AP, Miller JW, Bernal MT, D’Amico DJ, Folkman J, Yeo TK, Yeo KT (1994) Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 118:445–450PubMedGoogle Scholar
  48. 48.
    Poulsen JE (1953) Recovery from retinopathy in a case of diabetes with Simmonds’ disease. Diabetes 2:7–12PubMedGoogle Scholar
  49. 49.
    Sharp PS, Fallon TJ, Brazier OJ, Sandler L, Joplin GF, Kohner EM (1987) Long-term follow-up of patients who underwent yttrium-90 pituitary implantation for treatment of proliferative diabetic retinopathy. Diabetologia 30:199–207PubMedCrossRefGoogle Scholar
  50. 50.
    Wright AD, Kohner EM, Oakley NW, Hartog M, Joplin GF, Fraser TR (1969) Serum growth hormone levels and the response of diabetic retinopathy to pituitary ablation. Br Med J 2:346–348PubMedGoogle Scholar
  51. 51.
    Langford K, Nicolaides K, Miell JP (1998) Maternal and fetal insulin-like growth factors and their binding proteins in the second and third trimesters of human pregnancy. Hum Reprod 13:1389–1393PubMedCrossRefGoogle Scholar
  52. 52.
    Lassarre C, Hardouin S, Daffos F, Forestier F, Frankenne F, Binoux M (1991) Serum insulin-like growth factors and insulin-like growth factor binding proteins in the human fetus. Relationships with growth in normal subjects and in subjects with intrauterine growth retardation. Pediatr Res 29:219–225PubMedGoogle Scholar
  53. 53.
    Reece EA, Wiznitzer A, Le E, Homko CJ, Behrman H, Spencer EM (1994) The relation between human fetal growth and fetal blood levels of insulin-like growth factors I and II, their binding proteins, and receptors. Obstet Gynecol 84:88–95PubMedGoogle Scholar
  54. 54.
    Hellstrom A, Perruzzi C, Ju M, Engstrom E, Hard AL, Liu JL, Albertsson-Wikland K, Carlsson B, Niklasson A, Sjodell L, LeRoith D, Senger DR, Smith LE (2001) Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: direct correlation with clinical retinopathy of prematurity. Proc Natl Acad Sci USA 98:5804–5808PubMedCrossRefGoogle Scholar
  55. 55.
    Hellstrom A, Engstrom E, Hard AL, Albertsson-Wikland K, Carlsson B, Niklasson A, Lofqvist C, Svensson E, Holm S, Ewald U, Holmstrom G, Smith LE (2003) Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Pediatrics 112:1016–1020PubMedCrossRefGoogle Scholar
  56. 56.
    Lofqvist C, Engstrom E, Sigurdsson J, Hard AL, Niklasson A, Ewald U, Holmstrom G, Smith LE, Hellstrom A (2006) Postnatal head growth deficit among premature infants parallels retinopathy of prematurity and insulin-like growth factor-1 deficit. Pediatrics 117:1930–1938PubMedCrossRefGoogle Scholar
  57. 57.
    Smith LE (2004) Pathogenesis of retinopathy of prematurity. Growth Horm IGF Res 14(Suppl A):S140–S144PubMedCrossRefGoogle Scholar
  58. 58.
    Hellstrom A, Carlsson B, Niklasson A, Segnestam K, Boguszewski M, de Lacerda L, Savage M, Svensson E, Smith L, Weinberger D, Albertsson Wikland K, Laron Z (2002) IGF-I is critical for normal vascularization of the human retina. J Clin Endocrinol Metab 87:3413–3416PubMedCrossRefGoogle Scholar
  59. 59.
    Smith LE, Kopchick JJ, Chen W, Knapp J, Kinose F, Daley D, Foley E, Smith RG, Schaeffer JM (1997) Essential role of growth hormone in ischemia-induced retinal neovascularization. Science 276:1706–1709PubMedCrossRefGoogle Scholar
  60. 60.
    Smith LE, Shen W, Perruzzi C, Soker S, Kinose F, Xu X, Robinson G, Driver S, Bischoff J, Zhang B, Schaeffer JM, Senger DR (1999) Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med 5:1390–1395PubMedCrossRefGoogle Scholar
  61. 61.
    Kondo T, Vicent D, Suzuma K, Yanagisawa M, King GL, Holzenberger M, Kahn CR (2003) Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization. J Clin Invest 111:1835–1842PubMedCrossRefGoogle Scholar
  62. 62.
    Robitaille J, MacDonald ML, Kaykas A, Sheldahl LC, Zeisler J, Dube MP, Zhang LH, Singaraja RR, Guernsey DL, Zheng B, Siebert LF, Hoskin-Mott A, Trese MT, Pimstone SN, Shastry BS, Moon RT, Hayden MR, Goldberg YP, Samuels ME (2002) Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet 32:326–330PubMedCrossRefGoogle Scholar
  63. 63.
    Rehm HL, Zhang DS, Brown MC, Burgess B, Halpin C, Berger W, Morton CC, Corey DP, Chen ZY (2002) Vascular defects and sensorineural deafness in a mouse model of Norrie disease. J Neurosci 22:4286–4292PubMedGoogle Scholar
  64. 64.
    Xu Q, Wang Y, Dabdoub A, Smallwood PM, Williams J, Woods C, Kelley MW, Jiang L, Tasman W, Zhang K, Nathans J (2004) Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand–receptor pair. Cell 116:883–895PubMedCrossRefGoogle Scholar
  65. 65.
    Niehrs C (2004) Norrin and frizzled; a new vein for the eye. Dev Cell 6:453–454PubMedCrossRefGoogle Scholar
  66. 66.
    Ohlmann A, Scholz M, Goldwich A, Chauhan BK, Hudl K, Ohlmann AV, Zrenner E, Berger W, Cvekl A, Seeliger MW, Tamm ER (2005) Ectopic norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice. J Neurosci 25:1701–1710PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V. 2007

Authors and Affiliations

  1. 1.Department of OphthalmologyHarvard Medical School and Children’s Hospital BostonBostonUSA

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