June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
The Effects of VEGF and anti-VEGF on Outflow Facility in Mice and Humans
Author Affiliations & Notes
  • Darryl R Overby
    Bioengineering, Imperial College London, London, United Kingdom
  • Ester Reina-Torres
    Bioengineering, Imperial College London, London, United Kingdom
  • Joanne C Wen
    Ophthalmology, Duke University School of Medicine, Durham, NC
  • Katy Liu
    Ophthalmology, Duke University School of Medicine, Durham, NC
  • Guorong Li
    Ophthalmology, Duke University School of Medicine, Durham, NC
  • Joseph M Sherwood
    Bioengineering, Imperial College London, London, United Kingdom
  • R Rand Allingham
    Ophthalmology, Duke University School of Medicine, Durham, NC
  • W Daniel Stamer
    Ophthalmology, Duke University School of Medicine, Durham, NC
  • Footnotes
    Commercial Relationships Darryl Overby, None; Ester Reina-Torres, None; Joanne Wen, None; Katy Liu, None; Guorong Li, None; Joseph Sherwood, None; R Rand Allingham, None; W Stamer, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 3542. doi:
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    • Get Citation

      Darryl R Overby, Ester Reina-Torres, Joanne C Wen, Katy Liu, Guorong Li, Joseph M Sherwood, R Rand Allingham, W Daniel Stamer; The Effects of VEGF and anti-VEGF on Outflow Facility in Mice and Humans. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3542.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract
 
Purpose
 

Vascular endothelial growth factor (VEGF) regulates the permeability of vascular endothelia. VEGF is present in aqueous humor, and VEGF receptors are expressed by the endothelium of Schlemm’s canal (SC), but it remains unknown whether VEGF influences conventional outflow facility and thus intraocular pressure. The goal of this study was to test the hypotheses that (i) VEGF contributes to the physiologic regulation of conventional outflow facility in mice and (ii) that outflow facility is impaired in patients receiving anti-VEGF therapy for retinal disease.

 
Methods
 

Outflow facility was measured in freshly enucleated eyes from 30 C57BL/6 mice using a computerized iPerfusion system that was optimized for mouse eyes. Paired fellow eyes were perfused under one of three regimens (5 mice per condition): (i) VEGF-A­164a at 0.1, 0.5 or 1 µg/mL; (ii) with the inhibitory splice variant VEGF-A165b at 0.5 µg/mL; (iii) with inhibitors to VEGF receptor 2 (3 µM SU5416 or 1 nM Ki8751). VEGF secretion by TM and SC cells was measured by ELISA under static conditions or in TM cells following cyclic mechanical stretch for 24 hours or dexamethasone (DEX, 100 nM) for 7 days. Aqueous humor outflow facility was measured by tonography in 46 patients receiving unilateral bevacizumab, ranibizumab, or aflibercept as treatment for neovascular age-related macular degeneration independent of this study.

 
Results
 

VEGF165a increased facility by 74±30% at 0.1 μg/mL (mean ± SD; p=0.015) and by 59±23% at 0.5 μg/mL (p=0.004). However, 1 µg/mL decreased facility by 45±15% (p=0.003). VEGF165b decreased facility by 58±22% (p=0.02) at 0.5 μg/mL. In response to SU5416 and Ki8751, facility decreased by 55±19% and 40±20%, respectively (p < 0.01). TM and SC cells secreted VEGF under static conditions, and VEGF secretion by TM cells increased in response to stretch and DEX. In patients receiving more than 20 anti-VEGF injections, tonographic outflow facility was significantly lower in the treated eye relative to the untreated fellow eye (0.13 ± 0.05 vs. 0.15 ± 0.04 µL/min/mmHg; p = 0.01).

 
Conclusions
 

VEGF has a physiological role in the regulation of aqueous humor outflow facility, exhibiting a bi-phasic and isoform-specific response likely mediated in part by VEGF receptor 2. Inhibition of VEGF signaling reduces outflow facility and may contribute to sustained IOP elevation reported in a subset of patients receiving anti-VEGF therapy for retinal disease.

 
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