Altered mechanobiology of Schlemm's canal endothelial cells in glaucoma

• Type of Material: Article
• Authors: Darryl R. Overby, Imperial College London; Enhua H. Zhou, Harvard University; Rocio Vargas-Pinto, Northwestern University; Ryan M. Pedrigi, Imperial College London; Rudolf Fuchshofer, University of Regensburg; Sietse T. Braakman, Imperial College London; Ritika Gupta, Imperial College London; Kristin M. Perkumas, Duke University; Joseph M. Sherwood, Imperial College London; Amir Vahabikashi, Northwestern University; Dang Quynh, Harvard University; Jae Hun Kim, Harvard University; Ross Ethier, Emory University; W. Daniel Stamer, Duke University; Jeffrey J. Fredberg, Harvard University; Mark Johnson, Northwestern University
• Language: English
• Date: 2014-09-23
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: 2014 National Academy of Sciences
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1410602111
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• Volume: 111
• Issue: 38
• Start Page: 13876
• End Page: 13881
• Grant/Funding Information: We gratefully acknowledge support from the National Glaucoma Research program of the Bright Focus Foundation; National Institutes of Health Grants R01 EY 01969, R21 EY018373, and T32 EY007128; the Whitaker International Scholars Program; the Deutsche Forschungsgemeinschaft (FOR 1075, TP3); the Georgia Research Alliance; and the Royal Society Wolfson Research Excellence Award.; Northwestern University’s Atomic and Nanoscale Characterization Experimental Center (used for atomic force microscopy studies) is supported by the National Science Foundation-Nanoscale Science and Engineering Center, the National Science Foundation-Materials Research Science and Engineering Centers, the Keck Foundation, the State of Illinois, and Northwestern University.
• Keywords: STIFFNESS; TRABECULAR MESHWORK; MECHANICS; PORE DENSITY; modulus; RESISTANCE; Science & Technology - Other Topics; Multidisciplinary Sciences; cytoskeleton; cell mechanics; primary open-angle glaucoma; EYES; Science & Technology; INNER-WALL ENDOTHELIUM; MICROSCOPY; AQUEOUS-HUMOR OUTFLOW; CULTURE
• Research Categories: Biology, Anatomy; Health Sciences, Opthamology; Engineering, Biomedical

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.