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Nikita Ved, Richard Hulse, Samuel Bestall, Lucy Donaldson, James W B Bainbridge, David Bates; VEGF-A165b reduces vascular dysfunction in the diabetic retina. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):926.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic macular edema (DME) is associated with an increase in pro-angiogenic VEGF isoforms in the retina, notably VEGF-A165a, resulting in tight-junction degradation and vascular leakage. Anti-angiogenic isoforms, such as VEGF-A165b are down-regulated in the diabetic retina and this may contribute to the vascular dysfunction. The aim of this study is to assess the ability of VEGF-A165b to abrogate blood-retina barrier breakdown and subsequent hyperpermeability.
Human primary RPE cells were cultured in normal, low glucose (5mM) and high glucose (25mM) media +/- 2.5nM VEGF-A165b and assayed for tight junction integrity through occludin expression and trans-epithelial electrode resistance (TEER). ZO1 and occludin expression and TEER was used to assay RPE tight-junction integrity upon 2.5 nM VEGF-A165a treatment +/- 2.5 nM VEGF165b. In vivo retinal vascular dysfunction was measured in streptozotocin-induced diabetic rats (50mg/kg) after 1 week and 8 weeks of diabetes + / - VEGF-A165b (50ng intravitreally and 20ng/g intraperitoneally biweekly respectively). Evans’ blue extravasation and isolectin B4 staining was used to assess vascular permeability and neovascularisation respectively.
RPE cells cultured in 25mM media showed reduced occludin expression and increased paracellular flux that was restored with VEGF-A165b treatment. VEGF-A165a reduced occludin and ZO1 expression and increased paracellular flux, which were restored by VEGF-A165b. Diabetic rats treated with VEGF-A165b had reduced Evans’ blue extravasation at both 1 (p<0.05) and 8 (p<0.001) weeks post STZ-injection relative to vehicle treated diabetic rats.
VEGF165b is able to restore expression and function of tight junctions upon hyperglycaemic insult and may offer an effective therapeutic approach in treating diabetic macular edema.
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