Pathophysiology and mechanisms of severe retinopathy of prematurity

Abstract

Retinopathy of prematurity (ROP) affects only premature infants, but as premature births increase in many areas of the world, ROP has become a leading cause of childhood blindness. Blindness can occur from aberrant developmental angiogenesis that leads to fibrovascular retinal detachment. To treat severe ROP, it is important to study normal developmental angiogenesis and the stresses that activate pathologic signaling events and aberrant angiogenesis in ROP. Vascular endothelial growth factor (VEGF) signaling is important in both physiologic and pathologic developmental angiogenesis. Based on studies in animal models of oxygen-induced retinopathy (OIR), exogenous factors such as oxygen levels, oxidative stress, inflammation, and nutritional capacity have been linked to severe ROP through dysregulated signaling pathways involving hypoxia-inducible factors and angiogenic factors like VEGF, oxidative species, and neuroprotective growth factors to cause phases of ROP. This translational science review focuses on studies performed in animal models of OIR representative of human ROP and highlights several areas: mechanisms for aberrant growth of blood vessels into the vitreous rather than into the retina through over-activation of VEGF receptor 2 signaling, the importance of targeting different cells in the retina to inhibit aberrant angiogenesis and promote physiologic retinal vascular development, toxicity from broad and targeted inhibition of VEGF bioactivity, and the role of VEGF in neuroprotection in retinal development. Several future translational treatments are discussed, including considerations for targeted inhibition of VEGF signaling instead of broad intravitreal anti-VEGF treatment.

Figure 1

Human ROP: Human ROP is classified by zone, stage, and the presence of plus disease. To facilitate comparing phases of ROP (delayed physiologic retinal vascular development and vaso-proliferation) with experimental studies, ROP can be divided into early ROP, which comprises delayed physiologic retinal vascular development and stages 1 and 2 ROP; vascular ROP, which comprises stage 3 ROP and in severe ROP, plus disease; and fibrovascular ROP, which comprises stages 4 or 5 ROP with partial or total retinal detachment, respectively. ^**Drawing by James Gilman, CRA, FOPS

Figure 2. OIR models

Models of Mouse and Rat OIR showing oxygen profiles, phases 1 and 2 OIR and retinal flat mounts stained with lectin to visualize the vasculature.

Figure 3

Diagram of activated signaling pathways leading to the phases of human ROP based on experimental methods in the rat OIR model. Over activation of VEGFR2 can cause both phases of OIR and differential effects from STAT3 signaling based on the cell activated. Also targeted inhibition of VEGF in Müller cells can cause cell death and thinning of the outer nuclear layer.

Figure 4

a. Intravitreal Neovascularization (IVNV) grows aberrantly into the vitreous instead of into the retina. ^**Drawing by James Gilman, CRA, FOPS b. Endothelial cells grow into the vitreous as IVNV rather than into the retina as intraretinal blood vessels. The angle between the cleavage plane of dividing daughter cells and the long axis of the vessel predicts whether the vessel will be elongated or widened. One line of evidence shows that over activated VEGFR2 signaling disorders divisions of endothelial cells and permits their access to the vitreous cavity and diverts them from growing into the retina. ^**Drawing by James Gilman, CRA, FOPS

Figure 4

a. Intravitreal Neovascularization (IVNV) grows aberrantly into the vitreous instead of into the retina. ^**Drawing by James Gilman, CRA, FOPS b. Endothelial cells grow into the vitreous as IVNV rather than into the retina as intraretinal blood vessels. The angle between the cleavage plane of dividing daughter cells and the long axis of the vessel predicts whether the vessel will be elongated or widened. One line of evidence shows that over activated VEGFR2 signaling disorders divisions of endothelial cells and permits their access to the vitreous cavity and diverts them from growing into the retina. ^**Drawing by James Gilman, CRA, FOPS