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M. H. Elliott, M. E. McClellan, M. N. A. Mandal, J. D. Ash; Caveolin-1 Null Mice Display Increased Blood-Retinal Barrier Permeability. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1337.
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© ARVO (1962-2015); The Authors (2016-present)
Caveolin-1 (Cav-1) null mice have reduced retinal function by electroretinography. However, recordings from isolated rods indicated that phototransduction was normal, suggesting that ERG reductions were due to alteration of the photoreceptor environment. The purpose of this study was to determine if Cav-1 is essential for the maintenance of the photoreceptor environment including the blood-retinal barrier (BRB) and photoreceptor matrix.
BRB integrity was assessed by four assays. Permeability was measured in real-time in live mice using both fluorescence and magnetic resonance imaging. Localization of leakage was assessed by immunostaining of endogenous albumin and by confocal microscopic localization of exogenous, tailvein injected, AlexFluor 680-conjugated albumin and FITC-dextran (2 x 106 MW). We assessed Cav-1 expression in two retinal disease models including oxygen-induced retinopathy (OIR) and streptozotocin (STZ)-induced diabetes. Gene expression was compared between Cav-1 null and control mice by microarray and real-time PCR analyses.
Abnormal accumulation of albumin immunoreactivity was detected in retinas and vitreous of Cav-1 null mice compared to controls suggesting increased steady-state permeability of serum components. This increased permeability was detectable in vivo by both MRI and fluorescence analyses. AlexaFlour 680-albumin fluorescence localized to the outer retina and was most intense within the retinal pigmented epithelium in Cav-1 nulls. After OIR and STZ treatments, Cav-1 protein levels were reduced compared to room air or STZ-negative controls, respectively, further suggesting a relationship between Cav-1 levels and BRB permeability. Furthermore, Cav-1 null mice exposed to OIR displayed devastating loss of barrier integrity resulting in the infiltration of red blood cells from both the inner and outer BRB. Gene expression analyses suggest that inflammatory genes were significantly upregulated in Cav-1 null mice. Additional gene expression changes suggest matrix remodeling is increased in Cav-1 null animals.
Our results suggest that Cav-1 is essential for the maintenance of both the inner (endothelial) and outer (epithelial) BRB, and for maintaining normal extracellular matrix. Our results suggest that retinal levels of Cav-1 are reduced in diabetes and neovascular disease which may indicate its potential as a therapeutic target to treat these diseases.
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