The Biology of Retinopathy of Prematurity: How Knowledge of Pathogenesis Guides Treatment

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Key points

  • Review the molecular pathogenesis of retinopathy of prematurity (ROP).

  • Understand the role of the hypoxia-induced growth factors, particularly vascular endothelial growth factor, in the normal development of the retinal vasculature.

  • Understand the contribution of factors lacking after preterm birth, nutrition, insulinlike growth factor 1 and polyunsaturated fatty acids, in normal retinal development.

  • Describe clinical applications for the prevention/treatment of ROP, which have emerged from

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.

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