VEGF as a paracrine regulator of conventional outflow facility

Ester Reina-Torres, Joanne C. Wen, Katy C. Liu, Guorong Li, Joseph M. Sherwood, Jason Y.H. Chang, Pratap Challa, Cassandra M. Flügel-Koch, W. Daniel Stamer, R. Rand Allingham, Darryl R. Overby

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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-A164 a 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.

Original languageEnglish (US)
Pages (from-to)1899-1908
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number3
DOIs
StatePublished - Mar 2017
Externally publishedYes

Keywords

  • Mouse models
  • Outflow facility
  • Schlemm’s canal
  • Trabecular meshwork
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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