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Review the molecular pathogenesis of retinopathy of prematurity (ROP).
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Understand the role of the hypoxia-induced growth factors, particularly vascular endothelial growth factor, in the normal development of the retinal vasculature.
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Understand the contribution of factors lacking after preterm birth, nutrition, insulinlike growth factor 1 and polyunsaturated fatty acids, in normal retinal development.
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Describe clinical applications for the prevention/treatment of ROP, which have emerged from
The Biology of Retinopathy of Prematurity: How Knowledge of Pathogenesis Guides Treatment
Section snippets
Key points
Pathogenesis of ROP
What contributes to the susceptibility of the immature retina of the preterm infant and what are the differences between the in utero and extra uterine environment that contribute to the cessation of postnatal retinal vascular growth?
Phase I ROP: interruption of development with hyperoxia and undernutrition
Just as the formation of the retinal vasculature responds to “physiologic” hypoxia with developmental progression, it is sensitive to nonphysiologic hyperoxia, which is often encountered after preterm birth. The oxygen saturation of the fetus in the uterine environment is approximately 60% to 70%. Thus preterm birth into room air often causes an increase in oxygen saturation, which is further exacerbated by supplemental oxygen.23 Hyperoxia suppresses “physiologic hypoxia” causing downregulation
Phase II ROP
In severely affected infants, a proliferative phase (phase II) follows the vessel loss of Phase I.8 The degree of hypoxia and extent of avascular retina induced by phase I ROP determine the degree of hypoxia-derived proliferative factors, which determine the degree of phase II ROP. Phase II begins to develop after more than 32 postmenstrual weeks but can have a wide range of onset.25, 26 Even infants born at 32 weeks GA are susceptible to vessel loss when exposed to very high oxygen saturations
Animal Models of Oxygen-induced Retinopathy
Following the first description of the disease in the earliest studies,7, 28 animal studies have uncovered the molecular mediators of the effects of hyperoxia and hypoxia on retinal vascular development.23, 29, 30 Animal models of OIR have been developed in the neonatal kitten, dog, rat, and mouse. The mouse OIR model is currently the most commonly used model as it is reproducible, can be reliably quantified, and can be manipulated genetically (Fig. 2).24, 30
Hypoxia-induced factors and ROP: vascular endothelial growth factor
The role of the endothelial cell mitogen and vascular permeability factor VEGF, which plays a critical role in both phase I and phase II ROP, was first described in animal studies of OIR.21, 22, 30, 31, 32, 33, 34, 35, 36, 37
Phase I: VEGF is suppressed by hyperoxia, suppressing normal vessel growth
During retinal development, the wave front of “physiologic hypoxia” resulting from increasing metabolic demand of developing neurons, induces a wave of VEGF, which results in extension of forming vessels. The VEGF wave is suppressed with exposure to hyperoxia, causing cessation of normal vascular development seen in phase I of ROP.20, 29, 30, 31, 32, 36
In mouse OIR, after 6 hours exposure to 75% oxygen, both VEGF mRNA and protein levels are suppressed with loss of microvessels and cessation of
Clinical implications of VEGF and phase I of ROP
The finding above demonstrates that oxygen suppression of VEGF during phase I of ROP is a major contributor to vessel loss. These animal studies rationalize the judicious use of oxygen during the early postnatal period where there is incomplete retinal vascularization to minimize VEGF suppression to minimize vessel loss.
VEGF is Overexpressed in Phase II Causing Neovascularization
In the mouse OIR model, with return to room air, the now vasocompromised retina becomes hypoxic, which induces VEGF mRNA and protein expression,21 which are directly linked to aberrant neovascularization.21, 22, 34, 35
Clinical Implications of VEGF in Phase II of Retinopathy
Studies in the OIR model again help us understand the pathogenesis of phase II, showing that neovascularization can be inhibited by targeting VEGF in phase II with intravitreal injections of anti-VEGF compounds including antisense oligodeoxynucleotides, antibodies against VEGF, or
Insulinlike Growth Factor-1
Animal studies have been instrumental in understanding the influence of postnatal factors affecting vascular growth on the development of ROP.58 Specifically, IGF-1 has been shown to be critical in both phase I and phase II of retinopathy in the OIR model in the mouse.59, 60 IGF-1 is a polypeptide that promotes human fetal growth throughout gestation but particularly in the third trimester, IGF-I levels increase both in the maternal serum and in the fetus.61 Serum IGF-I levels correlate with
Summary
ROP is a clinically multifactorial process with potentially devastating effects on vision in premature infants. Prevention includes improved oxygen control with avoidance of fluctuations and provision of sufficient nutrition as early as possible. New preventative strategies including IGF-1 replacement and DHA supplementation and possible suppression of the hypoxia-related factor, VEGF, have been identified through insights into the molecular pathogenesis of ROP in animal studies. Any strategy
Acknowledgments
AH received support from the Swedish Medical Research Council (grant # 2011-2432), Government grants (#ALFGB-137491), VINNOVA (grant # 2009-00221). LEHS received support from Research to Prevent Blindness Sr. Investigator Award, NEI EY017017, NEI EY022275, NIH P01 HD18655, and the Lowy Medical Foundation.
References (79)
- et al.
Perinatal adaptation in mammals: the impact of metabolic rate
Comp Biochem Physiol A Mol Integr Physiol
(2007) Extreme prematurity and fibroblastic overgrowth of persistent vascular sheath behind each crystalline lens
Am J Ophthalmol
(1942)- et al.
Studies on the effect of high oxygen administration in retrolental fibroplasia. I. Nursery observations
Am J Ophthalmol
(1952) - et al.
Further observations on cost of preventing retrolental fibroplasia
Lancet
(1974) Retinal vascular development in premature infants
Am J Ophthalmol
(1977)- et al.
Randomized comparison of diode laser photocoagulation versus cryotherapy for threshold retinopathy of prematurity: seven-year outcome
Am J Ophthalmol
(2001) - et al.
Histopathology and vascular endothelial growth factor in untreated and diode laser-treated retinopathy of prematurity
J AAPOS
(1997) - et al.
Erythropoietin and VEGF exhibit equal angiogenic potential
Microvasc Res
(2002) - et al.
A double-edged sword: erythropoietin eyed in retinopathy of prematurity
J AAPOS
(2008) - et al.
Human recombinant erythropoietin and the incidence of retinopathy of prematurity: a multiple regression model
J AAPOS
(2008)
Insulin-like growth factor I concentrations in infancy predict differential gains in body length and adiposity: the Cambridge Baby Growth Study
Am J Clin Nutr
The insulin-like growth factors and feto-placental growth
Placenta
Circulating insulin-like growth factor I levels in newborn premature and full-term infants followed longitudinally
Early Hum Dev
Postnatal weight gain modifies severity and functional outcome of oxygen-induced proliferative retinopathy
Am J Pathol
Maternal and neonatal factors associated with poor early weight gain and later retinopathy of prematurity
Acta Paediatr
Longitudinal postnatal weight and insulin-like growth factor I measurements in the prediction of retinopathy of prematurity
Arch Ophthalmol
Early weight gain predicts retinopathy in preterm infants: new, simple, efficient approach to screening
Pediatrics
Validation of a new retinopathy of prematurity screening method monitoring longitudinal postnatal weight and insulinlike growth factor I
Arch Ophthalmol
Effect of oxygen on developing retinal vessels with particular reference to the problem of retrolental fibroplasia
Br J Ophthalmol
Increased 36-week survival with high oxygen saturation target in extremely preterm infants
N Engl J Med
Of Prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes
Pediatrics
High or low oxygen saturation and severe retinopathy of prematurity: a meta-analysis
Pediatrics
Twenty years of childhood blindness: what have we learnt?
Community Eye Health
Childhood blindness in the context of VISION 2020–the right to sight
Bull World Health Organ
Characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: implications for screening programs
Pediatrics
Astrocyte-endothelial cell relationships during human retinal vascular development
Invest Ophthalmol Vis Sci
Vascularization of the human fetal retina: roles of vasculogenesis and angiogenesis
Invest Ophthalmol Vis Sci
The effect of oxygen on vasoformative cell division. Evidence that ‘physiological hypoxia’ is the stimulus for normal retinal vasculogenesis
Invest Ophthalmol Vis Sci
Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization
Proc Natl Acad Sci U S A
Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity
Arch Ophthalmol
Animal models of oxygen-induced retinopathy
Front Biosci
Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture
Invest Ophthalmol Vis Sci
The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study
Pediatrics
Natural history of retinopathy of prematurity in infants born before 27 weeks' gestation in Sweden
Arch Ophthalmol
Aggressive posterior retinopathy of prematurity in large preterm babies in South India
Arch Dis Child Fetal Neonatal Ed
Intensive oxygen therapy as a possible cause of retrolental fibroplasia; a clinical approach
Med J Aust
Retinopathy of prematurity
Angiogenesis
Oxygen-induced retinopathy in the mouse
Invest Ophthalmol Vis Sci
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L.E. Smith, A. Hellström: These authors contributed equally to the work.