The Angio-Fibrotic Switch of VEGF and CTGF in Proliferative Diabetic Retinopathy

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.

A review of anti-VEGF agents for proliferative diabetic retinopathy

“…This can cause rising CTGF levels and thus promote a switch from angiogenesis to fibrosis. 47 Arevalo et al 45 reported that 82% of TRD developed within 5 days of injection. The highest incidence of progression of pre-existing TRD has been reported as 18% over a 2-30-day period.…”

Connective Tissue Growth Factor Regulates Retinal Neovascularization through p53 Protein-dependent Transactivation of the Matrix Metalloproteinase (MMP)-2 Gene

“…Furthermore, in vitro assays showed that CTGF/CCN2 may physically interact with VEGF and reduce the angiogenic activity of VEGF (57). These findings prompted other investigators to introduce the concept of a fibro-angiogenic switch that hypothetically occurs as excesses of CTGF/CCN2 suppress angiogenesis through formation of inactive CTGF/CCN2-VEGF complexes and activate fibrosis instead (58).…”

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“…35 Such damage can lead to rapid formation of tractional retinal detachment. 35,36 Guidance for ranibizumab therapy Monotherapy vs combination therapy Initiating ranibizumab monotherapy is the preferred approach for visual impairment due to DME. As yet, the role of adjunctive laser is unclear.…”