Enhancement of Outflow Facility in the Murine Eye by Targeting Selected Tight-Junctions of Schlemm's Canal Endothelia

• Type of Material: Article
• Authors: Lawrence C. Tam, University of Dublin; Ester Reina-Torres, University of Dublin; Joseph M. Sherwood, Imperial College London; Paul S. Cassidy, University of Dublin; Darragh E. Crosbie, University of Dublin; Elke Luetjen-Drecoll, University of Erlangen-Nürnberg; Cassandra Fluegel-Koch, University of Erlangen-Nürnberg; Kristin Perkumas, Duke University; Marian M. Humphries, University of Dublin; Anna-Sophia Kiang, University of Dublin; Jeffrey O'Callaghan, University of Dublin; John J. Callanan, Ross University School of Veterinary Medicine; A. Thomas Read, University of Toronto; Christopher Ethier, Emory University; Colm O'Brien, UCD School of Medicine; Matthew Lawrence, RxGen; Matthew Campbell, University of Dublin; W. Daniel Stamer, Duke University; Darryl R. Overby, Imperial College London; Pete Humphries, University of Dublin
• Language: English
• Date: 2017-01-16
• Publisher: Nature Publishing Group: Open Access Journals - Option C
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2017.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/srep40717
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 7
• Grant/Funding Information: The Unit also receives support from Science Foundation Ireland.; Work at the Ocular Genetics Unit at the University of Dublin, Trinity College, was supported by the European Research Council ERC-2012-AdG.; Work at Duke University was supported by grants from the US National Institutes of Health (EY022359 and EY019696) and at Imperial College London by Fight for Sight UK (Ref 1385), the US National Institutes of Health (EY022359 and EY019696), and the UK Engineering and Physical Sciences Research Council (EP/J010499/1).
• Keywords: BARRIER; AQUEOUS-HUMOR; TRABECULAR MESHWORK; FREEZE-FRACTURE; CELLS; INNER-WALL ENDOTHELIUM; MONKEY EYE; Science & Technology; INTERENDOTHELIAL JUNCTIONS; Science & Technology - Other Topics; Multidisciplinary Sciences; INTRAOCULAR-PRESSURE; PORE DENSITY
• Research Categories: Health Sciences, Opthamology; Engineering, Biomedical

Abstract

The juxtacanalicular connective tissue of the trabecular meshwork together with inner wall endothelium of Schlemm's canal (SC) provide the bulk of resistance to aqueous outflow from the anterior chamber. Endothelial cells lining SC elaborate tight junctions (TJs), down-regulation of which may widen paracellular spaces between cells, allowing greater fluid outflow. We observed significant increase in paracellular permeability following siRNA-mediated suppression of TJ transcripts, claudin-11, zonula-occludens-1 (ZO-1) and tricellulin in human SC endothelial monolayers. In mice claudin-11 was not detected, but intracameral injection of siRNAs targeting ZO-1 and tricellulin increased outflow facility significantly. Structural qualitative and quantitative analysis of SC inner wall by transmission electron microscopy revealed significantly more open clefts between endothelial cells treated with targeting, as opposed to non-targeting siRNA. These data substantiate the concept that the continuity of SC endothelium is an important determinant of outflow resistance, and suggest that SC endothelial TJs represent a specific target for enhancement of aqueous movement through the conventional outflow system.