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Liu Yang; Intraocular VEGF Deprivation Induces Inflammatory and Degenerative Response in Retina. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3871.
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© ARVO (1962-2015); The Authors (2016-present)
Vascular endothelial growth factor (VEGF) is a critical driver of ocular neovascularization under diseased conditions. Current therapeutic strategies depend on multiple intraocular injections of VEGF antagonizing reagents, which results in sustained deprivation of VEGF and suppression of pathogenic vascularization locally. Despite significant advancement has been achieved in preserving vision with therapeutic VEGF antagonism in last decade, substantial adverse effects have been reported in recent years with retrospective clinical studies. To understand mechanisms for intraocular VEGF deprivation associated adverse effects, we delivered recombinant adeno-associated virus encoding soluble Fms-related tyrosine kinase-1 (rAAV.sFLT-1), the extracellular domain of VEGF receptor, intravitreally in mice, followed by analysis of retinal tissues and function.
C57BL/6J mice were intravitreally injected with rAAV.sFLT-1, rAAV.mCherry or left untreated. Electroretinogram was performed to evaluate retinal response to visual stimulation. And the eye tissues were collected for immunofluorescence staining, apoptotis detection and gene expression analysis by RNA sequencing (RNA-seq) and qPCR. Pathway analyses were employed for further bioinformatic analyses.
Immunofluorescence staining revealed degenerative alterations of retina and activation of gliosis. Functional deficit in retinal response to visual stimulation was also recorded by electroretinogram in rAAV.sFLT-1 treated eyes as compared to control. Moreover, RNA-seq analysis confirmed activation of pro-inflammatory and degenerative pathways in VEGF-deprived retina and also implicates potential mechanisms for VEGF deprivation associated neurodegeneration, inflammation and other adverse effects.
Our findings demonstrate that sustained intraocular VEGF deprivation induces retinal inflammation and degeneration, which suggests that modulation of retinal response to sustained VEGF deprivation is beneficial to preserving visual function in long term.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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