Article

Signaling pathways triggered by oxidative stress that mediate features of severe retinopathy of prematurity.

Jama Ophthalmology (Impact Factor: 3.83). 01/2013; 131(1):80-5. DOI: 10.1001/jamaophthalmol.2013.986
Source: PubMed

ABSTRACT Oxidative stress has been implicated in the pathogenesis of retinopathy of prematurity for decades. It is becoming increasingly understood that reactive oxygen species can trigger signaling pathways that have beneficial or pathologic outcomes. Broad inhibition of reactive oxygen species in the preterm infant may lead to unwanted consequences, as has been experienced with vitamin E studies in the past. In this study, we provide a current understanding of the role of oxidative stress in activating signaling pathways that cause pathologic features in severe retinopathy of prematurity as it manifests in the era of oxygen regulation.

0 Followers
 · 
89 Views
  • Source
    05/2014; 44(2):223-226. DOI:10.4274/tjo.33254
  • Source
    [Show abstract] [Hide abstract]
    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.
    Ophthalmology 10/2014; 122(1). DOI:10.1016/j.ophtha.2014.07.050 · 6.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: NADPH oxidase 4 (Nox4) is a major isoform of NADPH oxidase in retinal endothelial cells. Our previous study suggests that upregulation of Nox4 in retinal endothelial cells contributes to retinal vascular leakage in diabetes. In the current study, we investigated the role and mechanism of Nox4 in regulation of retinal neovascularization (NV), a hallmark of proliferative diabetic retinopathy (PDR), using a mouse model of oxygen-induced retinopathy (OIR). Our results confirmed that Nox4 was expressed predominantly in retinal vasculature of mouse retina. Retinal expression of Nox4 was markedly increased in OIR, in parallel with enhanced phosphorylation of ERK. In human retinal microvascular endothelial cells (HRECs), overexpression of Nox4 by adenovirus significantly increased extracellular H2O2 generation, resulting in intensified VEGFR2 activation and exacerbated angiogenesis upon VEGF stimulation. In contrast, silencing Nox4 expression or scavenging H2O2 by polyethylene glycol- (PEG-) conjugated catalase inhibited endothelial migration, tube formation, and VEGF-induced activation of VEGFR2 signaling. Importantly, knockdown of retinal Nox4 by adenovirus-delivered siRNA significantly reduced ERK activation and attenuated retinal NV formation in OIR. Taken together, our data indicate that Nox4 promotes retinal NV formation through H2O2/VEGFR2/ERK signaling pathway. Reducing retinal Nox4 expression may represent a promising therapeutic approach for neovascular retinal diseases such as PDR.
    Journal of Diabetes Research 01/2015; 2015:963289. DOI:10.1155/2015/963289 · 3.54 Impact Factor