, Volume 48, Issue 11, pp 2422-2427
Date: 29 Sep 2005

Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor

Abstract

Aims/hypothesis

Proliferative diabetic retinopathy results from excess blood vessel growth into the vitreous fluid of the eye. Retinal angiogenesis is regulated by expression of vascular endothelial growth factor (VEGF), and many studies have shown that VEGF is critically involved in proliferative diabetic retinopathy. VEGF is alternatively spliced to form the angiogenic (VEGFxxx) and potentially anti-angiogenic (VEGFxxxb) family of isoforms. The VEGFxxxb family is found in normal tissues, but down-regulated in renal and prostate cancer. Previous studies on endogenous expression of VEGF in the eye have not distinguished between the two families of isoforms.

Methods

We measured VEGFxxxb isoform expression in normal human eye tissue (lens, sclera, retina and iris) and vitreous fluid using enzyme-linked immunosorbent assay and Western blotting with a VEGFxxxb-specific antibody.

Results

VEGFxxxb protein was expressed in lens, sclera, retina, iris and vitreous fluid. Multiple isoforms were seen, including VEGF165b, VEGF121b, VEGF145b, VEGF183b and VEGF189b. In non-diabetic patients, 64±7% of the VEGF in the vitreous was VEGFxxxb (n=18), whereas in diabetic patients only 12.5±3.6% of total VEGF was VEGFxxxb.

Conclusions/interpretation

Since VEGFxxxb inhibits VEGFxxx-induced angiogenesis in a one-to-one stoichiometric manner, these results show that in the eye of diabetic patients VEGF splicing was switched from an anti-angiogenic to a pro-angiogenic environment. This occurred through changes to the ratio of VEGFxxx : VEGFxxxb. Alterations to splicing, and through that to the balance of VEGF isoforms, could therefore be a potential therapeutic strategy for diabetic retinopathy.