The Effects of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Erythropoietin, and Their Interactions in Angiogenesis: Implications in Retinopathy of Prematurity

Abstract

Retinopathy of prematurity (ROP) is a leading cause of vision impairment and blindness in premature infants. Oxidative stress is implicated in its pathophysiology. NADPH oxidase (NOX), a major enzyme responsible for reactive oxygen species (ROS) generation in endothelial cells, has been studied for its involvement in physiologic and pathologic angiogenesis. Erythropoietin (EPO) has gained interest recently due to its tissue protective and angiogenic effects, and it has been shown to act as an antioxidant. In this review, we summarize studies performed over the last five years regarding the role of various NOXs in physiologic and pathologic angiogenesis. We also discuss the effect of EPO in tissue and vasoprotection, and the intersection of EPO and NOX-mediated oxidative stress in angiogenesis and the pathophysiology of ROP.

Systemic Cytokines in Retinopathy of Prematurity

“…When exposed to a hypoxic environment, hypoxia-inducible factor (HIF)-1α stabilizes and promotes the expression of VEGF, along with other pro-angiogenic factors. Other growth factors, such as erythropoietin (EPO) [ 72 , 73 , 74 ], IGF-1 [ 75 , 76 , 77 , 78 ], TGF-β [ 79 ], and FGF [ 71 , 80 ], enhance VEGF signaling [ 61 , 81 ]. Neurons and glial cells also modulate VEGF via the suppressor of cytokine signaling 3 (SOCS3) and signal transducer and activator of transcription 3 (STAT3) signaling pathways [ 82 ].…”

“…Its additional functions, such as neuroprotection [ 95 , 96 ], anti-apoptosis [ 97 , 98 ], anti-oxidation [ 99 ], angiogenesis promotion [ 100 ], and BRB maintenance [ 101 ], have also been discussed recently. Mainly modulated by HIF-2, EPO receptor (EPOR) signaling can also be enhanced by VEGF-A [ 102 ], along with the activation of nitric oxide synthase (NOS) in the pathological angiogenesis of ROP [ 72 , 73 , 74 ].…”

“…In ROP, EPO is regarded as a double-edged sword for its pro-angiogenic effect, which could be beneficial in the first phase of ROP when vaso-obliteration occurs due to hyperoxia, but is harmful in the second phase by aggravating abnormal neovascularization [ 103 , 104 ]. In mouse OIR models, hypoactive EPOR signaling contributes to retinal vascular loss under hyperoxia [ 73 , 74 , 103 , 104 ]. In addition, the administration of exogenous EPO could be beneficial in reducing the avascular retinal area [ 73 ], especially at an earlier period of life [ 103 , 104 ].…”

Pathophysiology of Retinopathy of Prematurity

“…Rats are less straightforward to genetically modify. Studying molecular mechanisms in the rat model can be done using gene therapy approaches with lentiviral, adenoviral, and adeno-associated viral vectors (for reviews, see Cung et al 2022, Wang et al 2013a). The dog model allows the study of vaso-obliteration and delay in retinal vascular development and has an ocular size more similar to the human infant eye than rodent models.…”

“…Lutein has not been effective when given to the premature infant (Cota et al 2022). Several protective compounds, including EPO, have not shown benefits in human trials (Cung et al 2022, Juul et al 2015, Soghier & Brion 2006. Additional research is important to understand the potential role of maternal-fetal effects and to protect the premature infant, whose antioxidant enzyme system is immature and who lacks antioxidants normally received from the maternal circulation in full-term birth.…”