Intraocular VEGF deprivation induces degeneration and fibrogenic response in retina

Xiao, Meichun; Liu, Yang; Wang, Lingyu; Liang, Jian; Wang, Tianjun; Zhai, Yadi; Wang, Yafang; Liu, Shu; Liu, Wenjia; Luo, Xueting; Wang, Fenghua; Sun, Xiaodong

doi:10.1096/fj.201901283rr

Cited by 6 publications

(3 citation statements)

References 79 publications

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“…To assess the retinal function of Cyp4v3 knockout mice and the littermate controls, full-field ERG was recorded using an RETIport System (Roland Consult, Brandenburg, Germany) with a Super Color Ganzfeld (Q450 SC) stimulator as described previously ( Xiao et al, 2019 ). After dark adaptation overnight, experimental mice were anesthetized with 1% sodium pentobarbital intraperitoneally, and pupils were dilated with 1% tropicamide.…”

Section: Methodsmentioning

confidence: 99%

A novel and efficient murine model of Bietti crystalline dystrophy

Wang

Yang

Liu

et al. 2022

Disease Models &Amp; Mechanisms

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Bietti crystalline dystrophy (BCD) is an autosomal recessive inherited retinal disease, resulting in blindness in most patients. The etiology and development mechanism of it remain unclear. Given the defects in previous mouse models of BCD, we generated a new Cyp4v3−/− mouse model, using CRISPR/Cas9 technology, for investigating the pathogenesis of BCD. We estimated the ocular phenotypes by fundus imaging, optical coherence tomography (OCT) and full-field scotopic electroretinography, and investigated the histological features by Hematoxylin and Eosin staining, Oil Red O staining and immunofluorescence. This model effectively exhibited age-related progression that mimicked the human ocular phenotypes. Moreover, gas chromatography-mass spectrometry and RNA-seq analysis indicated that the defect of Cyp4v3 led to the abnormal lipid metabolism, inflammation activation and oxidative stress of retina. Notably, inflammation activation and oxidative stress could also promote the progression of BCD in light-induced retinal degeneration. In conclusion, our data provided evidence that we established a novel and more effective Cyp4v3 knockout preclinical mouse model for BCD, which served as a useful tool for evaluating the effect of drugs and gene therapy in vivo.

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Section: Methodsmentioning

confidence: 99%

A novel and efficient murine model of Bietti crystalline dystrophy

Wang

Yang

Liu

et al. 2022

Disease Models &Amp; Mechanisms

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“…Full-field electroretinography (ERG) was recorded to assess the retinal function using RETIport System (Roland Consult, Brandenburg, Germany) with a Super Color Ganzfeld (Q450 SC) stimulator as previously described. 15 After dark adaptation overnight, experimental mice were anesthetized with 1% sodium pentobarbital intraperitoneally. Afterwards, 1% tropicamide and benoxinate HCl 0.4% eye drops were used for pupil dilation and local anesthesia.…”

Section: Electroretinographymentioning

confidence: 99%

Retinal degeneration in mice lacking the cyclic nucleotide‐gated channel subunit CNGA1

et al. 2021

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Cyclic nucleotide-gated (CNG) channels are important mediators in the transduction pathways of rod and cone photoreceptors. Native CNG channels are heterotetramers composed of homologous A and B subunits. Biallelic mutations in CNGA1 or CNGB1 genes result in autosomal recessive retinitis pigmentosa (RP).To investigate the pathogenic mechanism of CNG channel-associated retinal degeneration, we developed a mouse model of CNGA1 knock-out using CRISPR/ Cas9 technology. We observed progressive retinal thinning and a concomitant functional deficit in vivo as typical phenotypes for RP. Immunofluorescence and

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“…The formation of intraocular neovascularization is main cause of ophthalmological visual loss caused by age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), central retinal vein occlusion (CRVO), and other eye diseases [1][2][3]. At present, the main treatment is anti-vascular endothelial growth factor (anti-VEGF) in the treatment of intraocular neovascularization.…”

Section: Backgroudmentioning

confidence: 99%

P53/DRAM/ autophagy - a new target for improving the therapeutic effect of anti-VEGF on intraocular neovascularization

Wang

Yao²,

et al. 2020

Preprint

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Backgroud Recurrence of intraocular neovascularization is a major clinical problem. Anti-VEGF drugs are the main treatment for intraocular neovascularization currently. However, anti-VEGF drugs can activate endothelial autophagy and weaken the therapeutic effect. This study aims to elucidate the effect and mechanism of anti-VEGF drugs on autophagy of vascular endothelial cells. Methods RF/6A cells were randomly divided into five groups: The control group, hypoxia group (1% O2、5% CO2、94% N2), anti-VEGF group(group1:Ranibizumab 100ug/ml; group2: Aflibercept, 400ug/ml; group3: Conbercept, 100ug/ml) and autophagy inhibition group(3-MA or CQ) which was corresponding to anti-VEGF group. Autophagy-related proteins were examined by Western blot. RFP-GFP-LC3 was used to detect autophagy and autophagic flow. CCK-8 assay was used to detect cell proliferation. Flow cytometry and Tunel was used to detect cell apoptosis. Cell migration and tube formation were assessed by wound assay and matrix method, respectively. Results Ranibizumab and Conbercept can triger autophagy in hypoxia condition in RF/6A cells, while Aflibercept can inhibit autophagy. Conbercept combined with autophagy inhibitor (3-MA or CQ) could inhibit cell migration and tube formation of RF/6A cells more effectively in hypoxia condition. For mechanism, p53 and DRAM proteins paly an important role in Conbercept induced autophagy. Inhibition of P53 can suppressed the autophagy induced by Conbercept. Conclusion Ranibizumab and Conbercept can triger the autophagy of vascular endothelial cells while Aflibercept can inhibit it. The combination of ranibizumab/ Concept and autophagy inhibitor can significantly inhibit the formation of angiogenesis in vitro. The mechanism of autophagy activation is related to the activation of p53 / DRAM pathway.

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Intraocular VEGF deprivation induces degeneration and fibrogenic response in retina

Cited by 6 publications

References 79 publications

A novel and efficient murine model of Bietti crystalline dystrophy

A novel and efficient murine model of Bietti crystalline dystrophy

Retinal degeneration in mice lacking the cyclic nucleotide‐gated channel subunit CNGA1

P53/DRAM/ autophagy - a new target for improving the therapeutic effect of anti-VEGF on intraocular neovascularization

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