ROP is multifactorial in origin, with incomplete retinal vascularization as a consequence of prematurity a prerequisite. Retinal vascular development begins prior to 16 weeks gestation and grows steadily from the optic nerve toward the ora serrata. Vascular development of the immature, incompletely vascularized retina is highly influenced by systemic oxygen concentration levels and is regulated in part by vascular endothelial growth factor (VEGF).
Normal vasculogenesis during early fetal development is determined by local “physiological” hypoxia as a consequence of increasing retinal thickness, which creates an increase in metabolic demand in advance of the developing intraretinal vessels. Astrocytes in this hypoxic leading edge respond by secreting VEGF that promotes vascular development to meet the increasing metabolic demand of the maturing avascular retina, resulting in normal vasculogenesis from the optic nerve to the ora serrata.
The prematurely born neonate is exposed to dramatically elevated oxygen levels (relative to intrauterine physiologic oxygen concentration), resulting in retinal hyperoxia, vasospasm, and shutdown of sections of the developing retinal vasculature. ROP occurs as a result of this oxidative insult, which inhibits normal retinal vasculogenesis of the maturing avascular retina. The ensuing retinal ischemia stimulates a reactive overproduction of VEGF, which leads to the pathologic vasculogenesis known as ROP.
Transforming growth factor beta (tGF-beta) is a naturally occurring down-regulator of VEGF. An increase in endogenous tGF-beta production as the infant approaches 40 weeks post-menstrual age serves to down-regulate ROP. tGF beta is also a very potent scarring agent and is responsible for the cicatricial features of advanced ROP. There is increasing evidence that poor early weight gain and resultant low serum insulin-like growth factor I (IGF-I) also play an important role in ROP pathogenesis.
Insulin-like growth factor-1 (IGF-1) has also been implicated in controlling VEGF activation where low levels of IGF-1 prevent vascular development. Oxygen-independent IGF-1 and oxygen-dependent VEGF are complementary and synergistic vascular signaling mechanisms.
Genetic factors may play a role in the development of severe ROP as well. Some clinical features of ROP noted in near-term and full-term infants may resemble those seen in familial exudative vitreoretinopathy (FEVR), the X-linked form of which is associated with mutations in the Norrie disease (NDP) gene. Shastry et al investigated a cohort of 16 premature infants with ROP and found missense mutations in four infants with advanced disease. None of the parents or 50 healthy controls had mutations. The NDP gene product, norrin, is a ligand that activates a signal transduction pathway necessary for early retinal development and vasculogenesis. Subsequent studies have suggested up to 2% of infants with ROP have NDP mutations. It is likely that other genes involved in this signal transduction pathway may harbor mutations or polymorphisms that predispose premature babies to increased rates of ROP.
In the normally developing eye, regression of the vitreohyaloidal vascular network occurs concurrently with retinal vasculogenesis. Imbalances of VEGF and other growth factors may also impair normal regression of the hyaloid system and tunica vasculosa lentis, impacting vitreous development and organization in the developing neonate as well.
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