title: VEGF as a Paracrine Regulator of Conventional Outflow Facility.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Bioengineering, Imperial College London, London, United Kingdom.
authors.forename: Ester
authors.initials: E
authors.lastname: Reina-Torres
authors.affiliation: Department of Ophthalmology, Duke University, Durham, North Carolina, United States.
authors.forename: Joanne C
authors.initials: JC
authors.lastname: Wen
authors.affiliation: Department of Ophthalmology, Duke University, Durham, North Carolina, United States.
authors.forename: Katy C
authors.initials: KC
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Duke University, Durham, North Carolina, United States.
authors.forename: Guorong
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Bioengineering, Imperial College London, London, United Kingdom.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Sherwood
authors.affiliation: Department of Bioengineering, Imperial College London, London, United Kingdom.
authors.forename: Jason Y H
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Department of Ophthalmology, Duke University, Durham, North Carolina, United States.
authors.forename: Pratap
authors.initials: P
authors.lastname: Challa
authors.affiliation: Department of Anatomy II, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Cassandra M
authors.initials: CM
authors.lastname: Flügel-Koch
authors.affiliation: Department of Ophthalmology, Duke University, Durham, North Carolina, United States.
authors.forename: W Daniel
authors.initials: WD
authors.lastname: Stamer
authors.affiliation: Department of Ophthalmology, Duke University, Durham, North Carolina, United States.
authors.forename: R Rand
authors.initials: RR
authors.lastname: Allingham
authors.affiliation: Department of Bioengineering, Imperial College London, London, United Kingdom.
authors.forename: Darryl R
authors.initials: DR
authors.lastname: Overby
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D007429:Intraocular Pressure / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009798:Ocular Hypertension / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014129:Trabecular Meshwork / Q000166:cytology / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A