title: Altered mechanobiology of Schlemm's canal endothelial cells in glaucoma.
abstract: Increased flow resistance is responsible for the elevated intraocular pressure characteristic of glaucoma, but the cause of this resistance increase is not known. We tested the hypothesis that altered biomechanical behavior of Schlemm's canal (SC) cells contributes to this dysfunction. We used atomic force microscopy, optical magnetic twisting cytometry, and a unique cell perfusion apparatus to examine cultured endothelial cells isolated from the inner wall of SC of healthy and glaucomatous human eyes. Here we establish the existence of a reduced tendency for pore formation in the glaucomatous SC cell--likely accounting for increased outflow resistance--that positively correlates with elevated subcortical cell stiffness, along with an enhanced sensitivity to the mechanical microenvironment including altered expression of several key genes, particularly connective tissue growth factor. Rather than being seen as a simple mechanical barrier to filtration, the endothelium of SC is seen instead as a dynamic material whose response to mechanical strain leads to pore formation and thereby modulates the resistance to aqueous humor outflow. In the glaucomatous eye, this process becomes impaired. Together, these observations support the idea of SC cell stiffness--and its biomechanical effects on pore formation--as a therapeutic target in glaucoma.
authors.affiliation: Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom;
authors.forename: Darryl R
authors.initials: DR
authors.lastname: Overby
authors.affiliation: Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115;
authors.forename: Enhua H
authors.initials: EH
authors.lastname: Zhou
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208;
authors.forename: Rocio
authors.initials: R
authors.lastname: Vargas-Pinto
authors.affiliation: Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom;
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Pedrigi
authors.affiliation: Institute of Human Anatomy and Embryology, Universität Regensburg, 93053 Regensburg, Germany;
authors.forename: Rudolf
authors.initials: R
authors.lastname: Fuchshofer
authors.affiliation: Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom;
authors.forename: Sietse T
authors.initials: ST
authors.lastname: Braakman
authors.affiliation: Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom;
authors.forename: Ritika
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Department of Ophthalmology, Duke University, Durham, NC 27710;
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Perkumas
authors.affiliation: Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom;
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Sherwood
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208;
authors.forename: Amir
authors.initials: A
authors.lastname: Vahabikashi
authors.affiliation: Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115;
authors.forename: Quynh
authors.initials: Q
authors.lastname: Dang
authors.affiliation: Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115;
authors.forename: Jae Hun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332; Departments of Biomedical Engineering and Ophthalmology, Emory University, Atlanta, GA 30322;
authors.forename: C Ross
authors.initials: CR
authors.lastname: Ethier
authors.affiliation: Department of Ophthalmology, Duke University, Durham, NC 27710; Department of Biomedical Engineering, Duke University, Durham, NC 27710; and.
authors.forename: W Daniel
authors.initials: WD
authors.lastname: Stamer
authors.affiliation: Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115;
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Fredberg
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208; Departments of Mechanical Engineering and Ophthalmology, Northwestern University, Evanston, IL 60208 m-johnson2@northwestern.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
mesh_terms: D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005123:Eye / Q000378:metabolism / Q000473:pathology; D005901:Glaucoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018625:Microscopy, Atomic Force
keywords: cell mechanics; cytoskeleton; modulus; primary open-angle glaucoma