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S. F. Abcouwer, C.-M. Lin, E. B. Wolpert, S. Shanmugam, W. M. Freeman, E. W. Schaefer, A. J. Barber, T. W. Gardner, D. A. Antonetti; Vascular Permeability and Apoptosis Are Separable Processes in Ischemia-Reperfusion Retinopathy: Effects of Preconditioning and Bevacizumab. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3657.
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This study compared the effects of ischemic preconditioning (IPC) and targeting vascular endothelial growth factor (VEGF) on retinal apoptosis, vascular permeability and mRNA biomarker expression in a model of transient retinal ischemia followed by reperfusion (IR).
Sprague-Dawley rats were subjected to 45 minutes of retinal ischemia through elevated intraocular pressure, followed by reperfusion for various times up to 48 h. VEGF expression was quantified by Western blotting. IPC was induced by 10 min of ischemia 24 h prior to IR. Intravitreal injection of bevacizumab (Avastin®) 48 h prior to IR was used to block retinal VEGF function. Retinal neuronal apoptosis was quantified by measuring caspase-3 (DEVDase) activity and DNA fragmentation. Vascular permeability was quantified by measuring the accumulation of Evan’s Blue dye in retinal tissue. A set of 35 mRNA biomarkers with IR-responsive expression was identified and utilized to examine treatment responses.
IR caused significant increases in retinal VEGF protein expression, cell apoptosis, and Evan’s blue dye accumulation that persisted for at least 48 h. IPC abrogated apoptosis, but did not significantly affect Evan’s blue accumulation. Bevacizumab effectively inhibited accumulation of Evan’s blue, but did not affect apoptosis. IPC altered the IR responses of 15 mRNAs, while bevacizumab affected the IR responses of only 2 of the mRNA biomarkers.
IR provides an acute model of ischemic retinopathy that includes neurodegeneration and VEGF-dependent vascular permeability. The distinct effects of IPC and bevacizumab demonstrate that the apoptotic and vascular pathologies may require separate therapeutic interventions. Blocking VEGF did not induce apoptosis or exacerbate the ischemic effect on neurodegeneration, supporting the use of bevacizumab to treat vascular permeability in retinal disease.
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