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VEGF as a paracrine regulator of conventional outflow facility

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Title: VEGF as a paracrine regulator of conventional outflow facility
Authors: Overby, DR
Item Type: Journal Article
Abstract: Purpose: Vascular endothelial growth factor (VEGF) regulates microvascular endothelial permeability, and the permeability of Schlemm's canal (SC) endothelium influences conventional aqueous humor outflow. We hypothesize that VEGF signaling regulates outflow facility. Methods: We measured outflow facility (C) in enucleated mouse eyes perfused with VEGF-A164a, VEGF-A165b, VEGF-D, or inhibitors to VEGF receptor 2 (VEGFR-2). We monitored VEGF-A secretion from human trabecular meshwork (TM) cells by ELISA after 24 hours of static culture or cyclic stretch. We used immunofluorescence microscopy to localize VEGF-A protein within the TM of mice. Results: VEGF-A164a increased C in enucleated mouse eyes. Cyclic stretch increased VEGF-A secretion by human TM cells, which corresponded to VEGF-A localization in the TM of mice. Blockade of VEGFR-2 decreased C, using either of the inhibitors SU5416 or Ki8751 or the inactive splice variant VEGF-A165b. VEGF-D increased C, which could be blocked by Ki8751. Conclusions: VEGF is a paracrine regulator of conventional outflow facility that is secreted by TM cells in response to mechanical stress. VEGF affects facility via VEGFR-2 likely at the level of SC endothelium. Disruption of VEGF signaling in the TM may explain why anti-VEGF therapy is associated with decreased outflow facility and sustained ocular hypertension.
Issue Date: 1-Mar-2017
Date of Acceptance: 14-Feb-2017
URI: http://hdl.handle.net/10044/1/45053
DOI: https://dx.doi.org/10.1167/iovs.16-20779
ISSN: 1552-5783
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Start Page: 1899
End Page: 1908
Journal / Book Title: Investigative Ophthalmology & Visual Science
Volume: 58
Issue: 3
Copyright Statement: © 2017 The Authors. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/)
Sponsor/Funder: Engineering & Physical Science Research Council (EPSRC)
National Institutes of Health
BrightFocus Foundation
Fight For Sight
Funder's Grant Number: EP/J010499/1
Ref: 1385
Keywords: Ophthalmology & Optometry
11 Medical And Health Sciences
06 Biological Sciences
Publication Status: Published
Open Access location: http://iovs.arvojournals.org/article.aspx?articleid=2616207
Appears in Collections:Bioengineering
Faculty of Engineering