Angio-Fibrotic Switch 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. doi:10.1371/journal.pone.0002675.g004 membranes, CTGF is localized in retinal pigment epithelial cells [23], which are capable of transdifferentiation into myofibroblasts, the major cell type driving fibrosis. In fibrovascular membranes of patients with PDR and in human diabetic retina, CTGF is localized in myofibroblasts [24] and pericytes [37] which can also transform into myofibroblasts. Finally, in a recent study, it was not only shown that activated human hyalocytes and Mu¨ ller cells produce CTGF, but also that CTGF does not induce pro- angiogenic functions in cultured human endothelial cells [44]. In summary, our results suggest that, in contrast to VEGF, elevated CTGF levels do not significantly contribute to ocular angiogenesis in PDR. In addition, we propose that CTGF, in a critical balance with VEGF, drives the angio-fibrotic switch and subsequent fibrosis in PDR. This indicates that CTGF-targeted therapy is a possible novel option to prevent sight-threatening fibrosis in PDR and other ocular diseases that are associated with neovascularization and fibrosis. Our concept of the regulation of References 1. Aiello LP, Gardner TW, King GL, Blankenship G, Cavallerano JD, et al. (1998) Diabetic retinopathy. Diabetes Care 21: 143–156. 2. Campochiaro PA (2001) Pathogenesis of proliferative vitreoretinopathy. In: Ryan SJJ, ed. Retina. 3 ed. St. Louis: Mosby. pp 2221–2227. 3. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, et al. (2003) Diabetic retinopathy. Diabetes Care 26: 226–229. 4. Fong DS, Aiello LP, Ferris FL 3rd, Klein R (2004) Diabetic retinopathy. Diabetes Care 27: 2540–2553. 5. Hinton DR, He S, Jin ML, Barron E, Ryan SJ (2002) Novel growth factors involved in the pathogenesis of proliferative vitreoretinopathy. Eye 16: 422–428. 6. Cui JZ, Chiu A, Maberley D, Ma P, Samad A, et al. (2007) Stage specificity of novel growth factor expression during development of proliferative vitreoretino- pathy. Eye 21: 200–208. 7. Aiello LP, Bursell SE, Clermont A, Duh E, Ishii H, et al. (1997) Vascular endothelial growth factor-induced retinal permeability is mediated by protein the angio-fibrotic switch processes outside the eye. Author Contributions may also apply to wound healing Conceived and designed the experiments: EJK RG ROS. Performed the experiments: EJK. Analyzed the data: MWT. Contributed reagents/ materials/analysis tools: MDD JCV. Wrote the paper: EJK ROS. Overall responsibility for the coordination of the study: EJK. Collection of vitreous samples: EJK MDD JCV. Performed laboratory experiments: EJK. Interpretation of results: EJK FAV MDD JCV NO IK CJV RG. Preparation of the first drafts of the manuscript: EJK. Optimization of CTGF-ELISA and measurement of CTGF in vitreous samples: FAV. Supervision of all statistics: MWT. Supply of reagents: NO. Supervision of the laboratory experiments: IK. Preparation of the last version of the manuscript and supervision of the preparation of the manuscript: CJV. Supervision of part of the laboratory experiments: RG. Design of the study: ROS RG. Overall supervision of data collection: ROS. kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 46: 1473–1480. 8. Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO (2003) Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res 22: 1–29. 9. Gariano RF, Gardner TW (2005) Retinal angiogenesis in development and disease. Nature 438: 960–966. 10. Kuiper EJ, De Smet MD, Van Meurs JC, Tan HS, Tanck MW, et al. (2006) Association of connective tissue growth factor with fibrosis in vitreoretinal disorders in the human eye. Arch Ophthalmol 124: 1457–1462. 11. Franklin TJ (1997) Therapeutic approaches to organ fibrosis. Int J Biochem Cell Biol 29: 79–89. 12. Goldschmeding R, Aten J, Ito Y, Blom I, Rabelink T, et al. (2000) Connective tissue growth factor: just another factor in renal fibrosis? Nephrol Dial Transplant 15: 296–299. PLoS ONE | www.plosone.org 6 July 2008 | Volume 3 | Issue 7 | e2675