Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life

Abstract

Retinopathy of prematurity (ROP) is a major complication of preterm birth. It encompasses a spectrum of pathologies that affect vision, from mild disease that resolves spontaneously to severe disease that causes retinal detachment and subsequent blindness. The pathologies are characterized by an arrest in normal retinal vascular development associated with microvascular degeneration. The resulting ischemia and retinal hypoxia lead to excessive abnormal compensatory blood vessel growth. However, this neovascularization can lead to fibrous scar formation and culminate in retinal detachment. Present therapeutic modalities to limit the adverse consequences of aberrant neovascularization are invasive and/or tissue-destructive. In this Review, we discuss current concepts on retinal microvascular degeneration, neovascularization, and available treatments, as well as present future perspectives toward more profound elucidation of the pathogenesis of ROP.

Figure 1. Overview of the pathogenesis of ROP.

Schematic depiction of the neural retina and the vascular beds that perfuse it. Retinal vessels (which form preretinal vascular tufts in ROP) are present adjacent to the retinal ganglion cell layer next to the vitreous body. As ROP progresses, there is an initial phase of vascular degeneration (vasoobliteration), followed by a secondary phase of compensatory (but pathologic) angiogenesis toward the vitreous of the retina (preretinal neovascularization). The choroidal vascular plexus, which supplies the outer retina and is affected in age-related macular degeneration, is present behind the photoreceptors at the back of the eye. RPE, retinal pigment epithelium.

Figure 2. Deficient autoregulation in the premature retina.

Deficient autoregulation of ocular blood flow in the newborn fails to limit retinal oxygenation during hyperoxia. This results in excess delivery of oxygen to tissues. High carbon dioxide tension increases ocular blood flow and further curtails its autoregulation. Increased retinal oxygenation augments free radical generation and suppresses VEGF expression in the newborn. This leads to arrest in vascular development and microvascular degeneration. The ensuing ischemia triggers the aberrant neovascularization seen in ROP.

Figure 3. The effects of hypercapnia on RBF.

Sustained hypercapnia evokes a marked increase in RBF. This effect is sequentially mediated by calcium entry into endothelial cells, inducing increased PGE₂ production and in turn eNOS-derived NO formation.

Figure 4. The effects of oxidant stress on premature retinal vasculature.

The premature retina is relatively deficient in antioxidants. Consequently, oxidant stress is more likely to induce peroxidation and nitration that is cytotoxic to retinal microvasculature. Downstream mediators of peroxidation, notably the phospholipids PAF and LPA, the non-enzymatically derived prostanoids, isoprostanes, and nitration products (of particular relevance here are the trans-AAs) are all cytotoxic to retinovascular endothelium, causing vasoobliteration. PGS, PG synthase; TXS, thromboxane synthase.

Figure 5. The proangiogenic effects of metabolite signaling in ROP.

During hypoxia, as seen in ROP/OIR following hyperoxia-induced microvascular degeneration, succinate accumulates. Through its actions on its receptor, GPR91, which is present on retinal ganglion cells (RGCs), succinate induces production of a pleiotropy of proangiogenic factors, which trigger neovascular formation. This new vessel growth attempts to restore oxygen supply to the hypoxic retina; however, in ROP this compensatory vascular expansion is exaggerated and penetrates the vitreous. ANG-2, angiopoietin 2.

Figure 6. Summary illustration of the current concepts in ROP.

When premature birth occurs, the retinal vasculature, which normally develops until birth, is immature. In addition, the premature infant is deficient in several maternally derived factors (such as ω-3 PUFAs and IGF-1, which are transferred during the third trimester) that are essential for healthy blood vessel development, thus further compromising the prognosis. Moreover, the premature patient is mechanically ventilated to overcome pulmonary insufficiencies, and as a consequence, the supplemental oxygen given during mechanical ventilation contributes to retinal vascular obliteration due to oxidant stress and suppression of oxygen-regulated proangiogenic factors such as VEGF and Epo. Following the initial phase of vascular dropout, a second phase of compensatory and destructive neovascularization results and is driven by hypoxia-induced angiogenic factors. Current therapeutic interventions rely on invasive procedures such as laser photocoagulation, whereby affected areas of the retina are cauterized. A number of future treatments, including anti-VEGF therapy and the use of antioxidants, are currently being evaluated.