Abstract
PurposeVascular 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.MethodsWe 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.ResultsVEGF-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.ConclusionsVEGF 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.
Highlights
Vascular endothelial growth factor (VEGF) regulates microvascular endothelial permeability, and the permeability of Schlemm’s canal (SC) endothelium influences conventional aqueous humor outflow
VEGF is a paracrine regulator of conventional outflow facility that is secreted by trabecular meshwork (TM) cells in response to mechanical stress
Disruption of VEGF signaling in the TM may explain why anti-VEGF therapy is associated with decreased outflow facility and sustained ocular hypertension
Summary
We measured outflow facility (C) in enucleated mouse eyes perfused with VEGFA164a, VEGF-A165b, VEGF-D, or inhibitors to VEGF receptor 2 (VEGFR-2). Perfusion of enucleated mouse eyes was used to assess the effect of VEGF or related compounds on pressure-dependent outflow facility. Outflow facility (C) was measured in paired contralateral eyes by multilevel constant pressure perfusion using iPerfusion.[45] All mice were male C57BL/6 (Charles River UK Ltd, Margate, UK) aged between 9 and 13 weeks at the time of perfusion. The eye was pressurized at 8 mm Hg for 45 minutes to allow the eye to equilibrate to the perfusion system and provide time for the drug to permeate through the anterior chamber and outflow pathway. Intraocular pressure was measured using a differential pressure transducer (PX409; Omegadyne, Sunbury, OH, USA), while the flow rate into the eye was measured using a thermal flow sensor (SLG64-0075; Sensirion, Staefa, Switzerland) as previously described.[45]
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