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Michael H Elliott, Xiaowu Gu, Nicole E Ashpole, Gina L. Griffith, Timothy M Boyce, Masaki Tanito, Ernst R Tamm, W Daniel Stamer; Role of Caveolin-1 in Intraocular Pressure and Conventional Outflow Regulation. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2888.
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© ARVO (1962-2015); The Authors (2016-present)
Gene association studies have linked polymorphisms in the CAV1/2 gene locus to risk of primary open angle glaucoma. The proteins encoded by these genes are the signature structural proteins of caveolae plasma membrane domains that are abundant in the conventional outflow pathway including Schlemm’s canal endothelium and trabecular meshwork. The purpose of this study was to test consequences of caveolin-1 (Cav-1) ablation on intraocular pressure (IOP), conventional outflow, and outflow pathway morphology.
Global Cav-1 knockout (KO) mice and age/sex-matched controls were used for these studies. Intraocular pressure was measured by rebound tonometry (Tonolab), outflow facility was measured in perfused enucleated eyes using a constant flow perfusion system customized for mice, and outflow tissue morphology was assessed by light and transmission electron microscopy.
A significant elevation in IOP was observed in Cav-1 KO mice at 5 weeks of age and was sustained at 3 and 6 months. Pressure-dependent outflow, measured at 4 sequentially increasing pressure steps (8, 15, 25, 35 mmHg), was significantly reduced by 43% in Cav-1 KO mice compared to controls (0.045 ± 0.012 versus 0.079 ± 0.005 µl/min/mmHg; p ≤ 0.05, n = 9 KO and 8 control eyes). Ultrastructural analysis revealed a loss of morphologically-identifiable caveolae. Schlemm’s canal endothelial cells were considerably thicker and shorter than in controls, and protruded into the lumen of the canal. Typical giant vacuoles were absent.
Results provide compelling evidence that Cav-1 and caveolae play important roles in conventional outflow and thus IOP regulation. Understanding the mechanism by which Cav-1 controls pressure-dependent outflow has important clinical implications for both the pathobiology and treatment of glaucoma.
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