The angio-fibrotic switch of VEGF and CTGF in proliferative diabetic retinopathy - PubMed (original) (raw)

The angio-fibrotic switch of VEGF and CTGF in proliferative diabetic retinopathy

Esther J Kuiper et al. PLoS One. 2008.

Abstract

Background: 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/principal findings: 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 (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/significance: CTGF 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.

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Conflict of interest statement

Competing Interests: Noelynn Oliver is an employee of Fibrogen Inc, Roel Goldschmeding has received research support grants from Fibrogen Inc.

Figures

Figure 1

Figure 1. Correlation between the levels of CTGF and log10(VEGF) in the vitreous of all 68 patients.

A significant (p = 0.01) Spearman's rank correlation (ρ = 0.4) within all samples was found.

Figure 2

Figure 2. Mean levels of CTFG (A, D), geometric mean levels of VEGF (B, E), and mean ratio CTGF/log10(VEGF) (C, F) in relation with degree of neovascularization (A–C) and degree of fibrosis (D–F) in the vitreous of 32 PDR patients.

Vertical bars represent 95% confidence intervals. Significant differences between groups are indicated.

Figure 3

Figure 3. Fundus photographs of a patient with proliferative diabetic retinopathy and new vessels (nv) along the lower vascular arcade, before (A) and 8 months after (B) an injection with bevacizumab followed by pan-retinal photocoagulation.

Note the increase in fibrosis (f) after anti-VEGF and laser treatment (B).

Figure 4

Figure 4. Fundus photographs (A, D) and fluorescein angiographic imaging (B, C) of a patient with branch retinal vein occlusion before (A–C) and after (D) treatment with pan-retinal photocoagulation.

Note the leaky vessels consistent with angiogenesis(A, C), and the quiet aspect of the vessels after treatment without formation of fibrosis (D). n, normal; nv, neovascularization.

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