title: Enhancement of Outflow Facility in the Murine Eye by Targeting Selected Tight-Junctions of Schlemm's Canal Endothelia.
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.
authors.affiliation: Neurovascular Genetics, Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin 2, Ireland.
authors.forename: Lawrence C S
authors.initials: LC
authors.lastname: Tam
authors.affiliation: Neurovascular Genetics, Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin 2, Ireland.|Department of Bioengineering, Imperial College London, London, UK.
authors.forename: Ester
authors.initials: E
authors.lastname: Reina-Torres
authors.affiliation: Department of Bioengineering, Imperial College London, London, UK.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Sherwood
authors.affiliation: Neurovascular Genetics, Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin 2, Ireland.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Cassidy
authors.affiliation: Neurovascular Genetics, Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin 2, Ireland.
authors.forename: Darragh E
authors.initials: DE
authors.lastname: Crosbie
authors.affiliation: Department of Anatomy, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Lütjen-Drecoll
authors.affiliation: Department of Anatomy, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Flügel-Koch
authors.affiliation: Department of Ophthalmology, Duke University, Durham, NC, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Perkumas
authors.affiliation: Neurovascular Genetics, Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin 2, Ireland.
authors.forename: Marian M
authors.initials: MM
authors.lastname: Humphries
authors.affiliation: Neurovascular Genetics, Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin 2, Ireland.
authors.forename: Anna-Sophia
authors.initials: AS
authors.lastname: Kiang
authors.affiliation: Neurovascular Genetics, Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin 2, Ireland.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: O'Callaghan
authors.affiliation: Ross University School of Veterinary Medicine, P. O. Box 334, Basseterre, St. Kitts, West Indies.
authors.forename: John J
authors.initials: JJ
authors.lastname: Callanan
authors.affiliation: Department of Ophthalmology and Vision Sciences, University of Toronto, Canada.
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Read
authors.affiliation: Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, USA.
authors.forename: C Ross
authors.initials: CR
authors.lastname: Ethier
authors.affiliation: Ophthalmology, Mater Hospital, UCD School of Medicine, Dublin, Ireland.
authors.forename: Colm
authors.initials: C
authors.lastname: O'Brien
authors.affiliation: RxGen, Hamden, CT, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Lawrence
authors.affiliation: Neurovascular Genetics, Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin 2, Ireland.
authors.forename: Matthew
authors.initials: M
authors.lastname: Campbell
authors.affiliation: Department of Ophthalmology, Duke University, Durham, NC, USA.
authors.forename: W Daniel
authors.initials: WD
authors.lastname: Stamer
authors.affiliation: Department of Bioengineering, Imperial College London, London, UK.
authors.forename: Darryl R
authors.initials: DR
authors.lastname: Overby
authors.affiliation: Neurovascular Genetics, Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin 2, Ireland.
authors.forename: Pete
authors.initials: P
authors.lastname: Humphries
mesh_terms: D000818:Animals; D000867:Anterior Chamber / Q000502:physiology*; D001082:Aqueous Humor / Q000378:metabolism*; D015415:Biomarkers; D042783:Endothelial Cells / Q000378:metabolism / Q000648:ultrastructure; D004727:Endothelium / Q000378:metabolism* / Q000648:ultrastructure; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D010539:Permeability; D011323:Primates; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D015415:Biomarkers; D034741:RNA, Small Interfering