Postnatal hyperoxia and the developing rat retina: beyond the obvious vasculopathy

Dorfman, Allison; Chemtob, Sylvain; Lachapelle, Pierre

doi:10.1007/s10633-009-9208-3

Cited by 12 publications

(14 citation statements)

References 19 publications

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“…13, 17, 18 It also has been shown that hyperoxia causes neuronal death in brain 19 and retina. 24 Hence, it is important to investigate retinal cell death in the OIR retina during the hyperoxic phase. In the present study, we analyzed hyperoxia-induced retinal apoptosis using terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

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Arginase 2 deficiency reduces hyperoxia-mediated retinal neurodegeneration through the regulation of polyamine metabolism

Narayanan

Putluri

et al. 2014

Cell Death Dis

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Hyperoxia treatment has been known to induce neuronal and glial death in the developing central nervous system. Retinopathy of prematurity (ROP) is a devastating disease in premature infants and a major cause of childhood vision impairment. Studies indicate that, in addition to vascular injury, retinal neurons are also affected in ROP. Using an oxygen-induced retinopathy (OIR) mouse model for ROP, we have previously shown that deletion of the arginase 2 (A2) significantly reduced neuro-glial injury and improved retinal function. In the current study, we investigated the mechanism of A2 deficiency-mediated neuroprotection in the OIR retina. Hyperoxia treatment has been known to induce neuronal death in neonates. During the hyperoxia phase of OIR, a significant increase in the number of apoptotic cells was observed in the wild-type (WT) OIR retina compared with A2-deficient OIR. Mass spectrometric analysis showed alterations in polyamine metabolism in WT OIR retina. Further, increased expression level of spermine oxidase was observed in WT OIR retina, suggesting increased oxidation of polyamines in OIR retina. These changes were minimal in A2-deficient OIR retina. Treatment using the polyamine oxidase inhibitor, N, N′-bis (2, 3-butadienyl)-1, 4-butanediamine dihydrochloride, significantly improved neuronal survival during OIR treatment. Our data suggest that retinal arginase is involved in the hyperoxia-induced neuronal degeneration in the OIR model, through the regulation of polyamine metabolism.

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Section: Resultsmentioning

confidence: 99%

“…21, 22, 23 Hyperoxia-induced defects in retinal neural function have been reported in neonatal rats. 24 …”

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confidence: 99%

Arginase 2 deficiency reduces hyperoxia-mediated retinal neurodegeneration through the regulation of polyamine metabolism

Narayanan

Putluri

et al. 2014

Cell Death Dis

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“…The inner retina has long been considered to be the primary region affected in human ROP and animal models. 42 Lately, dysfunctions of photoreceptors are detected in a significant number of older children formerly afflicted with ROP; these outer retinal dysfunctions are composed of defective dark adaptation because of rod dysfunction, 3 abnormal cone function, 43 and retinal depigmentation. 44 Moreover, the apparent progressive nature of these changes is suggested.…”

Section: Discussionmentioning

confidence: 99%

Choroidal Involution Is Associated with a Progressive Degeneration of the Outer Retinal Function in a Model of Retinopathy of Prematurity

Zhou

Rivera

Bhosle

et al. 2016

The American Journal of Pathology

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Retinopathy of prematurity (ROP), the most common cause of blindness in premature infants, has long been associated with inner retinal alterations. However, recent studies reveal outer retinal dysfunctions in patients formerly afflicted with ROP. We have recently demonstrated that choroidal involution occurs early in retinopathy. Herein, we investigated the mechanisms underlying the choroidal involution and its long-term impact on retinal function. An oxygen-induced retinopathy (OIR) model was used. In vitro and ex vivo assays were applied to evaluate cytotoxic effects of IL-1β on choroidal endothelium. Electroretinogram was used to evaluate visual function. We found that proinflammatory IL-1β was markedly increased in retinal pigment epithelium (RPE)/choroid and positively correlated with choroidal degeneration in the early stages of retinopathy. IL-1β was found to be cytotoxic to choroid in vitro, ex vivo, and in vivo. Long-term effects on choroidal involution included a hypoxic outer neuroretina, associated with a progressive loss of RPE and photoreceptors, and visual deterioration. Early inhibition of IL-1β receptor preserved choroid, decreased subretinal hypoxia, and prevented RPE/photoreceptor death, resulting in life-long improved visual function in IL-1 receptor antagonist-treated OIR animals. Together, these findings suggest a critical role for IL-1β-induced choroidal degeneration in outer retinal dysfunction. Neonatal therapy using IL-1 receptor antagonist preserves choroid and prevents protracted outer neuroretinal anomalies in OIR, suggesting IL-1β as a potential therapeutic target in ROP.

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“…The oxygen‐induced retinopathy (OIR) mouse model is the most widely used animal model to study ischemic neovascular retinopathies including retinopathy of prematurity and late neovascular proliferative diabetic retinopathy (Smith et al ; Stahl et al ). As in human ischemic retinopathy patients, retinal function is markedly impaired in OIR mice (Stahl et al ; Dorfman et al ; Vessey et al ; Ridano et al ; Matsuda et al ). Moreover these mice also exhibit reduced numbers of dopaminergic amacrine cells (Spix et al ) and delayed intermediate vascular plexus formation (Ritter et al ; Spix et al ).…”

mentioning

confidence: 99%

VEGF‐Trap is a potent modulator of vasoregenerative responses and protects dopaminergic amacrine network integrity in degenerative ischemic neovascular retinopathy

Arias

Economopoulou

López

et al. 2019

Journal of Neurochemistry

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Retinal hypoxia triggers abnormal vessel growth and microvascular hyper‐permeability in ischemic retinopathies. Whereas vascular endothelial growth factor A (VEGF‐A) inhibitors significantly hinder disease progression, their benefits to retinal neurons remain poorly understood. Similar to humans, oxygen‐induced retinopathy (OIR) mice exhibit severe retinal microvascular malformations and profound neuronal dysfunction. OIR mice are thus a phenocopy of human retinopathy of prematurity, and a proxy for investigating advanced stages of proliferative diabetic retinopathy. Hence, the OIR model offers an excellent platform for assessing morpho‐functional responses of the ischemic retina to anti‐angiogenic therapies. Using this model, we investigated the retinal responses to VEGF‐Trap (Aflibercept), an anti‐angiogenic agent recognizing ligands of VEGF receptors 1 and 2 that possesses regulatory approval for the treatment of neovascular age‐related macular degeneration, macular edema secondary to retinal vein occlusion and diabetic macular edema. Our results indicate that Aflibercept not only reduces the severity of retinal microvascular aberrations but also significantly improves neuroretinal function. Aflibercept administration significantly enhanced light‐responsiveness, as revealed by electroretinographic examinations, and led to increased numbers of dopaminergic amacrine cells. Additionally, retinal transcriptional profiling revealed the concerted regulation of both angiogenic and neuronal targets, including transcripts encoding subunits of transmitter receptors relevant to amacrine cell function. Thus, Aflibercept represents a promising therapeutic alternative for the treatment of further progressive ischemic retinal neurovasculopathies beyond the set of disease conditions for which it has regulatory approval. Cover Image for this issue: doi: .

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Postnatal hyperoxia and the developing rat retina: beyond the obvious vasculopathy

Cited by 12 publications

References 19 publications

Arginase 2 deficiency reduces hyperoxia-mediated retinal neurodegeneration through the regulation of polyamine metabolism

Arginase 2 deficiency reduces hyperoxia-mediated retinal neurodegeneration through the regulation of polyamine metabolism

Choroidal Involution Is Associated with a Progressive Degeneration of the Outer Retinal Function in a Model of Retinopathy of Prematurity

VEGF‐Trap is a potent modulator of vasoregenerative responses and protects dopaminergic amacrine network integrity in degenerative ischemic neovascular retinopathy

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