Retinopathy of Prematurity-Targeting Hypoxic and Redox Signaling Pathways

Abstract

Retinopathy of prematurity (ROP) is a proliferative vascular ailment affecting the retina. It is the main risk factor for visual impairment and blindness in infants and young children worldwide. If left undiagnosed and untreated, it can progress to retinal detachment and severe visual impairment. Geographical variations in ROP epidemiology have emerged over recent decades, attributable to differing levels of care provided to preterm infants across countries and regions. Our understanding of the causes of ROP, screening, diagnosis, treatment, and associated risk factors continues to advance. This review article aims to present the pathophysiological mechanisms of ROP, including its treatment. Specifically, it delves into the latest cutting-edge treatment approaches targeting hypoxia and redox signaling pathways for this condition.

Keywords: molecular targets; novel; pathophysiology; retinopathy of prematurity; signaling pathways.

Figure 1

Illustration depicting the zones, stages, and types of ROP. Zone I encompasses the circular area centered on the optic nerve head, having a radius equal to twice the distance between the optic nerve and the fovea, while Zone II extends as a circle centered on the optic nerve head, presenting a radius equal to the distance between the optic nerve and nasal ora serrata. Zone III covers the peripherical retinal area, extending over Zone II. Stage 1 manifests as a demarcation line, delineating the boundary between the physiologically vascularized retina and the peripheral avascular retina. In Stage 2, this line progresses into a distinct ridge. Stage 3 marks the onset of extraretinal neovascularization and hemorrhages. Stage 4 indicates partial and stage 5 total retinal detachment, respectively. The plus disease is characterized by pronounced vascular dilation and tortuosity.

Figure 2

Schematic representation depicting the two pathogenetic phases in ROP, highlighting distinct expression levels of key mediators in the retina. ROP: retinopathy of prematurity; ROS: reactive oxygen species; O₂: oxygen; VEGF: vascular endothelial growth factor; IGF-1: insulin-like growth factor 1; EPO: erythropoietin; HIF-1α: hypoxia-inducible factor 1 alpha; MMP: metalloproteinase; Ang-2: angiopoietin 2. Upward black arrows indicate upregulation or increased concentration, downward black arrows indicate downregulation or decreased concentration.

Figure 3

Schematic overview depicting the primary molecular pathways activated during phases 1 and 2 in ROP. ROS: reactive oxygen species; NOX: nicotinamide adenine dinucleotide phosphate oxidase; O₂: oxygen; O₂∙⁻: superoxide; ONOO⁻: peroxynitrite; VEGF: vascular endothelial growth factor; EPO: erythropoietin; HIF-1α: hypoxia-inducible factor 1 alpha; BH₄: tetrahydrobiopterin; NO: nitric oxide; eNOS: endothelial nitric oxide synthase; STAT3: signal transducer and activator of transcription 3; RGC: retinal ganglion cell; RPE: retinal pigment epithelium; THBS1: thrombospondin 1. Upward black arrows indicate upregulation or increased concentration, downward black arrows indicate downregulation or decreased concentration.