Molecular basis of retinopathy of prematurity

Retinopathy of prematurity (ROP) is a major cause of blindness in children and is strongly related to premature birth. During 1980s and 1990s, cryotherapy and laser photocoagulation of the avascular retina were main treatments of this condition. However, after these interventions, the patients may still experience poor visual acuity. Preventive therapies for ROP are therefore desirable, and understanding the molecular basis of the disease is crucial to the development of such treatments.
ROP development can be divided into two phases: an initial phase of vessel loss (starting 30-32 weeks postmenstrual age) followed by a second phase of vessel proliferation (32-34 weeks postmenstrual age). Retinal blood vessel development starts from the center of the optic disc during the fourth month of gestation and reaches the retinal periphery just before birth. Therefore, infants born prematurely have incompletely vascularized retinas with a peripheral avascular zone. In premature infants, vascular growth that would normally occur in utero slows or ceases and is accompanied by regression of developed retinal vessels, most likely because of extrauterine hyperoxia and supplemental oxygen administration. As the infant matures, the non-vascularized retina becomes metabolically active. In the absence of an adequate vascular system, this leads to tissue hypoxia. The second phase of ROP is characterized by hypoxia-induced retinal pathological neovascularization, that eventually produces a fibrous scar extending from the retina to the vitreous gel and lens. Retraction of scar tissue can determine retinal detachment and blindness.
Vascular endothelial growth factor (VEGF) plays an essential role in the development of the retinal vasculature. This molecule is expressed by astrocytes in response to the hypoxia, in order to stimulate new blood vessels growth. Experimental studies show that suppression of VEGF in phase I of ROP inhibits vessel growth. In phase II, VEGF expression is increased in retina, resulting in pathological neovascularization. Inhibition of VEGF in this phase significantly decreases the neovascular response, confirming the importance of this molecule in neovascularization.
Moreover, it has been demonstrated that insulin-like growth factor-1 (IGF-1) serum levels in premature babies are directly correlated with the severity of clinical ROP. The expression of this molecule is directly linked with VEGF one. In fact, clinical studies have indicated that lack of IGF-1 in preterm infants prevents normal retinal vascular growth in phase I of ROP, despite the presence of VEGF. This suggest that IGF-1 may serve a permissive function, and that VEGF alone might not be sufficient for promoting vigorous retinal angiogenesis in phase I.
The discovery of the importance of VEGF and IGF-1 in the development of ROP is a step forward in our understanding of the pathogenesis of this disease and may suggest new therapeutic targets. For instance, the use of anti-VEGF therapy is the first medical treatment for neovascularization in age-related macular degeneration and is likely to be useful for ROP. The finding that late development of ROP is associated with low levels of IGF-1 after premature birth suggests that physiological replacement of IGF-1 to levels found in utero might prevent the disease by allowing normal vascular development. In addition, the use of a specific agonist to VEGF receptor might be used early in the disease process to prevent vessel loss without promoting proliferative disease. Further studies on disease mechanism and treatment strategies may lead to a significant improvement in  ROP management.

Top