Retinopathy of prematurity: Metabolic risk factors

Abstract

At preterm birth, the retina is incompletely vascularized. Retinopathy of prematurity (ROP) is initiated by the postnatal suppression of physiological retinal vascular development that would normally occur in utero. As the neural retina slowly matures, increasing metabolic demand including in the peripheral avascular retina, leads to signals for compensatory but pathological neovascularization. Currently, only late neovascular ROP is treated. ROP could be prevented by promoting normal vascular growth. Early perinatal metabolic dysregulation is a strong but understudied risk factor for ROP and other long-term sequelae of preterm birth. We will discuss the metabolic and oxygen needs of retina, current treatments, and potential interventions to promote normal vessel growth including control of postnatal hyperglycemia, dyslipidemia and hyperoxia-induced retinal metabolic alterations. Early supplementation of missing nutrients and growth factors and control of supplemental oxygen promotes physiological retinal development. We will discuss the current knowledge gap in retinal metabolism after preterm birth.

Keywords: hyperglycemia; medicine; retinal metabolism; retinopathy of prematurity.

Figure 1.. Schematics of ROP development (A) and illustration of human ROP development.

In ROP, hyperglycemia and hyperoxia causes retinal vessel growth cessation (Phase 1). As the neural retina matures, increasing nutrient and oxygen demand triggers retinal neovessel growth (Phase 2). Human neovascular ROP (Phase 2) develops through the following stages: stage 2 with ridge (arrow), stage 3 with neovascularization and hemorrhage (arrows), stage 3 with plus disease (dilation and tortuosity of vessels) (arrow), Aggressive posterior ROP (APROP) with central changes (arrow) is particularly pathological. Laser treatment (arrow) of stage 3 ROP is illustrated. Figure was reproduced from Figure 1 from Tomita et al., 2021b.

Figure 2.. VEGF in the pathogenesis of ROP.

During normal retinal vascular development, growth factor like VEGF (black dots) is found anterior to the developing vasculature driving the normal retinal vessel development forward. After preterm birth, in Phase I ROP, hyperoxia suppresses HIF-regulated growth factor (VEGF) production, causing vaso-obliteration and vessel growth cessation. As the retina matures with increasing metabolic demand, the non-perfused peripheral retina becomes hypoxic and nutrient deprived and overproduces growth factors (VEGF). Neovascularization occurs in response to high levels of growth factors. Images were created using BioRender, adapted and modified from ‘retina’, ‘dots’ by BioRender.com (2022).

Figure 3.. Schematics of mouse oxygen-induced retinopathy (OIR) and hyperglycemia-associated retinopathy (HAR).

In OIR, mouse pups and the nursing dam are exposed to 75% oxygen from postnatal day (P) 7 for 5 days causing vessel loss and cessation of vessel growth and returned to room air where the avascular retina becomes hypoxic and causes neovascularization. There is also a metabolic model of suppression of retinal vessel growth as seen in Phase I ROP. In HAR, mouse pups are given low dose streptozotocin (STZ 50 mg/kg) daily from P1 to P9, causing hyperglycemia which suppresses normal vascular development examined at P10. Images were created using BioRender, adapted and modified from “mouse” by BioRender.com (2022).

Figure 4.. O2 profiles through the dark-adapted retina of rhesus monkey.

A retinal depth of zero is the vitreoretinal border and 100% is the RPE-choroid border. The lowest oxygen tension is found in the layer containing photoreceptor inner segments with very high mitochondrial density. Rising oxygen tension across the inner retinal layers is due to three layers of inner retinal vasculature. Figure was reproduced from Figure 1 from Linsenmeier and Zhang, 2017. License number 5416050680408.

Figure 5.. Schematic of retinal neuronal and vascular structure.

RGC, retinal ganglion cells, RPE, retinal pigment epithelium. Images were created using BioRender, adapted and modified from ‘eye’, ‘retinal cell’, ‘generic branching vessel’ by BioRender.com (2022).