Abstract
BackgroundIn 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/Principal FindingsVEGF 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 (n = 4) were studied before and after pan-retinal photocoagulation and intra-vitreal injections with bevacizumab, an antibody against VEGF. Neovascularization and fibrosis in various degrees occurred almost exclusively in PDR patients. In PDR patients, vitreous CTGF levels were significantly associated with degree of fibrosis and with VEGF levels, but not with neovascularization, whereas VEGF levels were associated 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/SignificanceCTGF is primarily a pro-fibrotic factor in the eye, and a shift in the balance between CTGF and VEGF is associated with the switch from angiogenesis to fibrosis in proliferative retinopathy.
Highlights
Blindness from proliferative diabetic retinopathy (PDR) is caused by angiogenesis and fibrosis in the vitreous cavity of the eye [1,2,3,4]
Multivariate analysis showed that mean connective tissue growth factor (CTGF) levels were only associated with degree of fibrosis (p,0.001), whereas log10(VEGF) levels were only significantly associated with degree of neovascularization (p,0.001)
The observations presented in this study, set against the background of existing literature on vascular endothelial growth factor (VEGF) and CTGF, prompt us to propose a novel concept of the regulation of angiogenesis and fibrosis in ocular disease, and in wound healing in general
Summary
Blindness from proliferative diabetic retinopathy (PDR) is caused by angiogenesis and fibrosis in the vitreous cavity of the eye [1,2,3,4]. PDR is a wound healing-like response in which neovascularization is accompanied by influx of inflammatory cells and development of myofibroblasts. This progresses to a fibrotic phase with fibrovascular contraction causing haemorrhages, retinal detachment and inevitable blindness. 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
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