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C. Ergorul, Z. K. Luo, W. Huang, A. Ray, J. Fileta, D. Darland, C. L. Grosskreutz; Levels of VEGF-165b, a Recently Identified Inhibitory VEGF Isoform, Are Elevated in Experimental Glaucoma. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3274.
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Vascular Endothelial Growth Factor (VEGF) plays a causative role in neovascularization (NV) in ischemic retinopathies. Although ischemia has been implicated in the development of glaucoma, there is no NV in glaucoma and the role of VEGF has not been examined. VEGF-165b has recently been shown to be an endogenous inhibitor of VEGF-induced NV and we hypothesized that VEGF-165b levels would be elevated in glaucoma.
Intraocular pressure (IOP) was elevated unilaterally in Brown Norway rats by injecting hypertonic saline in the episcleral veins as described by Morrison. The contralateral eye served as the control. VEGF-165 and VEGF-165b protein levels were analyzed by immunoblot analysis in normal and glaucomatous retinas.
In control and glaucomatous retinas, VEGF-165 primary antibody recognized 23 and 46 kDa bands that coincide with the monomeric and dimeric forms of VEGF-165, respectively. The dimer levels of VEGF-165 increased significantly in glaucomatous retinas following 10 days of elevated IOP (mean ± SD) (2.59 ± 1.7 fold; n= 8; p<0.05). VEGF-165 monomer levels did not differ significantly between the control and glaucomatous retinas. Similarly, Western Blotting with VEGF-165b primary antibody revealed 23 and 46 kDa bands in control and glaucomatous retinas. These bands correspond to the monomeric and dimeric forms of VEGF-165b, respectively. VEGF-165b dimer levels increased significantly in glaucomatous retinas following 5 days (4.17 ± 1.6 fold; n= 6; p<0.05) and 10 days of elevated IOP (4.13 ± 2.4 fold; n= 6; p<0.05). The VEGF-165b monomer levels were not significantly different between the control and glaucomatous retinas.
There is a growing body of evidence that VEGF splice variants produce both pro-angiogenic and anti-angiogenic isoforms and a shift in splicing determines the outcome. Here we demonstrated that both VEGF-165 and VEGF-165b, an inhibitory anti-angiogenic VEGF isoform, are overexpressed in experimental glaucoma following elevated IOP. These data suggest that if ischemia contributes to the pathogenesis of glaucoma, the lack of NV may be a consequence of a concomitant elevation of VEGF-165b levels.
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