A novel model of persistent retinal neovascularization for the development of sustained anti-VEGF therapies

Li, Yong; Busoy, Joanna Marie; Zaman, Ben Alfyan Achirn; Tan, Queenie Shu Woon; Tan, Gavin Siew Wei; Barathi, Veluchamy A; Cheung, Ning; Wei, Jay; Hunziker, Walter; Hong, Wanjin; Wong, Tien Yin; Cheung, Chui Ming Gemmy

doi:10.1016/j.exer.2018.05.027

Cited by 33 publications

(26 citation statements)

References 34 publications

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“…The multifactoriality of ocular vasculopathies and adaptive resistance because of compensatory up‐regulation of factors other than VEGF‐A might represent a significant hurdle for VEGF‐A inhibitors that ultimately renders tissues non‐responsive to these agents. Such phenomenon is well‐described in tumor biology (Croci and Rabinovich ; Li et al ) and, in the context of neovascular retinopathies, might result in the persistence of visual deficits (Rakic et al ; Shih et al ; Cheung et al ; Hammes et al ; Gupta et al ; Semeraro et al ; Roy et al ; Ridano et al ) or lead to substantial visual decline in initial responders even several years after anti‐VEGF‐A treatment (Rofagha et al ). Interestingly, conventional anti‐VEGF‐A agents fail to restore visual function also in OIR mice, presumably because of compensatory up‐regulation of alternative angiogenic factors (Ridano et al ).…”

mentioning

confidence: 93%

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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mentioning

confidence: 93%

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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“…Overexpression of VEGF is a major cause of retinal neovascularization and vascular leakage. VEGF promotes migration, proliferation, and tube formation in human retinal endothelial cells (HRECs) through autocrine signaling, and it also regulates the cooperation of other cells during angiogenesis through paracrine signaling in the retina [5]. Thus, VEGF has been considered as a therapeutic target for antiangiogenesis in diabetic retinopathy [5,6].…”

Section: Introductionmentioning

confidence: 99%

Scutellarin Prevents Angiogenesis in Diabetic Retinopathy by Downregulating VEGF/ERK/FAK/Src Pathway Signaling

Long

et al. 2019

Journal of Diabetes Research

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Background. Diabetic retinopathy (DR) is a serious microvascular complication of diabetes. This study demonstrates the antiangiogenic effects of scutellarin (SCU) on high glucose- and hypoxia-stimulated human retinal endothelial cells (HRECs) and on a diabetic rat model by oral administration. The antiangiogenic mechanisms of SCU in vitro and in vivo were investigated. Method. HRECs were cultured in high glucose- (30 mM D-glucose) and hypoxia (cobalt chloride-treated)-stimulated diabetic condition to evaluate the antiangiogenic effects of SCU by CCK-8 test, cell migration experiment (wound healing and transwell), and tube formation experiment. A streptozotocin-induced type II diabetic rat model was established to measure the effects of oral administration of SCU on protecting retinal microvascular dysfunction by Doppler waveforms and HE staining. We further used western blot, luciferase reporter assay, and immunofluorescence staining to study the antiangiogenic mechanism of SCU. The protein levels of phospho-ERK, phospho-FAK, phospho-Src, VEGF, and PEDF were examined in HRECs and retina of diabetic rats. Result. Our results indicated that SCU attenuated diabetes-induced HREC proliferation, migration, and tube formation and decreased neovascularization and resistive index in the retina of diabetic rats by oral administration. SCU suppressed the crosstalk of phospho-ERK, phospho-FAK, phospho-Src, and VEGF in vivo and in vitro. Conclusions. These results suggested that SCU can be an oral drug to alleviate microvascular dysfunction of DR and exerts its antiangiogenic effects by inhibiting the expression of the crosstalk of VEGF, p-ERK, p-FAK, and p-Src.

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“…PRNV model was established as described. 19 In brief, PRNV was induced by a single intravitreal injection with 50 lL 0.025M DL-alpha-aminoadipic acid (DL-AAA) per eye. The establishment of PRNV was confirmed by fluorescein angiography.…”

Section: Persistent Retinal Neovascularization (Prnv) Rabbit Modelmentioning

confidence: 99%

“…To confirm the antiangiogenic effect of Apratoxin S4 in vivo, we investigated its impact on retinal neovascularization and leakage as observed in PDR, in a rabbit model of PRNV. 19 Rabbits with established PRNV received a single intravitreal injection of Apratoxin S4 (1.7 lM per eye in vitreous), which is four times lower than the amount of aflibercept (6.96 lM) used in this model. FFA was taken 3 days later to evaluate retinal neovascularization and leakage, which was compared with baseline FFA of the same eye before the treatment.…”

Section: Apratoxin S4 Inhibits Ocular Angiogenesis In Vivomentioning

confidence: 99%

Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases

Qiu

Tan

Veluchamy

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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A novel model of persistent retinal neovascularization for the development of sustained anti-VEGF therapies

Cited by 33 publications

References 34 publications

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

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

Scutellarin Prevents Angiogenesis in Diabetic Retinopathy by Downregulating VEGF/ERK/FAK/Src Pathway Signaling

Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases

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