The Angio-Fibrotic Switch in Proliferative Diabetic Retinopathy: A Balance Shift Between the Growth Factors VEGF and CTGF

Abstract

Purpose: : In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) cause blindness by neovascularization and subsequent fibrosis, but their relative contribution to both processes is unknown. We hypothesize that the balance between levels of pro-angiogenic VEGF and pro-fibrotic CTGF regulates angiogenesis, the angio-fibrotic switch, and the resulting fibrosis and scarring.

Methods: : VEGF and CTGF were measured by ELISA in 68 vitreous samples of patients with proliferative DR (PDR, N=32), macular hole (N=13) or macular pucker (N=23) and were related to clinical data, including degree of intra-ocular neovascularization and fibrosis. In addition, clinical cases of PDR were studied before and after pan-retinal photocoagulation and intra-vitreal injections with bevacizumab, an antibody against VEGF.

Results: : Neovascularization and fibrosis in various degrees occurred almost exclusively in PDR patients. In PDR patients, vitreous CTGF levels correlated significantly with degree of fibrosis and with VEGF levels, but not with neovascularization, whereas VEGF levels correlated only with neovascularization. The ratio of CTGF and VEGF was the strongest predictor of degree of fibrosis. As predicted by these findings, patients with PDR demonstrated a temporary increase in intra-ocular fibrosis after anti-VEGF treatment or laser treatment.

Conclusions: : CTGF is primarily a pro-fibrotic factor in the eye, and a shift in this balance between CTGF and VEGF causes the switch from angiogenesis to fibrosis in proliferative retinopathy.

Keywords: diabetic retinopathy • growth factors/growth factor receptors • vitreous