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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)
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.
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.
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).
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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