13. Perbal B (2004) CCN proteins: multifunctional signalling regulators. Lancet 363: 62–64. 14. Mageto Y, Flaherty K, Brwon K, Fong A, Raghu G (200) Safety and tolerability of human monoclonal antibody FG-3019, anti-connective tissue growth factor, in patients with idiopathic pulmonary fibrosis. Chest 126: 773S. 15. Van Nieuwenhoven FA, Jensen LJ, Flyvbjerg A, Goldschmeding R (2005) Imbalance of growth factor signalling in diabetic kidney disease: is connective tissue growth factor (CTGF, CCN2) the perfect intervention point? Nephrol Dial Transplant 20: 6–10. 16. He S, Jin ML, Worpel V, Hinton DR (2003) A role for connective tissue growth factor in the pathogenesis of choroidal neovascularization. Arch Ophthalmol 121: 1283–1288. 17. Suzuma K, Naruse K, Suzuma I, Takahara N, Ueki K, et al. (2000) Vascular endothelial growth factor induces expression of connective tissue growth factor via KDR, Flt1, and phosphatidylinositol 3-kinase-akt-dependent pathways in retinal vascular cells. J Biol Chem 275: 40725–40731. 18. Kuiper EJ, Hughes JM, Vogels IMC, Goldschmeding R, Van Noorden CJF, et al. (2007) Effect of VEGF-A on expression of pro-fibrotic growth factor and extracellular matrix genes in the retina. Invest Ophthalmol Vis Sci 48: 4267–4276. 19. Inoki I, Shiomi T, Hashimoto G, Enomoto H, Nakamura H, et al. (2002) Connective tissue growth factor binds vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis. FASEB J 16: 219–221. 20. Jang HS, Kim HJ, Kim JM, Lee YS, Kim KL, et al. (2004) A novel ex vivo angiogenesis assay based on electroporation-mediated delivery of naked plasmid DNA to skeletal muscle. Mol Ther 9: 464–474. 21. Babic AM, Chen CC, Lau LF (1999) Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo. Mol Cell Biol 19: 2958–2966. 22. Shimo T, Nakanishi T, Nishida T, Asano M, Kanyama M, et al. (1999) Connective tissue growth factor induces the proliferation, migration, and tube formation of vascular endothelial cells in vitro, and angiogenesis in vivo. J Biochem 126: 137–145. 23. Watanabe D, Takagi H, Suzuma K, Oh H, Ohashi H, et al. (2005) Expression of connective tissue growth factor and its potential role in choroidal neovascularization. Retina 25: 911–918. 24. Hinton DR, Spee C, He S, Weitz S, Usinger W, et al. (2004) Accumulation of NH(2)-terminal fragment of connective tissue growth factor in the vitreous of patients with proliferative diabetic retinopathy. Diabetes Care 27: 758–764. 25. Kuiper EJ, Roestenberg P, Ehlken C, Lambert V, Bloys van Treslong-de Groot H, et al. (2007) Angiogenesis is not impaired in connective tissue growth factor (CTGF)-knock out mice. J Histochem Cytochem 55: 1139–1147. 26. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, et al. (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331: 1480–1487. 27. Igarashi A, Nashiro K, Kikuchi K, Sato S, Ihn H, et al. (1995) Significant correlation between connective tissue growth factor gene expression and skin sclerosis in tissue sections from patients with systemic sclerosis. J Invest Dermatol 105: 280–284. 28. Igarashi A, Nashiro K, Kikuchi K, Sato S, Ihn H, et al. (1996) Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. J Invest Dermatol 106: 729–733. 29. Grotendorst GR (1997) Connective tissue growth factor: a mediator of TGF- beta action on fibroblasts. Cytokine Growth Factor Rev 8: 171–179. 30. Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, et al. (1999) Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model. J Cell Physiol 181: 153–159. 31. Moussad EE, Brigstock DR (2000) Connective tissue growth factor: what’s in a name? Mol Genet Metab 71: 276–292. 32. Kondo S, Kubota S, Shimo T, Nishida T, Yosimichi G, et al. (2002) Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases. Carcinogenesis 23: 769–776. Angio-Fibrotic Switch 33. Frank RN (1994) Vascular endothelial growth factor–its role in retinal vascular proliferation. N Engl J Med 331: 1519–1520. 34. Schlingemann RO, Van Hinsbergh VW (1997) Role of vascular permeability factor/vascular endothelial growth factor in eye disease. Br J Ophthalmol 81: 501–512. 35. Hofman P, Blaauwgeers HG, Tolentino MJ, Adamis AP, Nunes Cardozo BJ, et al. (2000) VEGF-A induced hyperpermeability of blood-retinal barrier endothelium in vivo is predominantly associated with pinocytotic vesicular transport and not with formation of fenestrations. Vascular endothelial growth factor-A. Curr Eye Res 21: 637–645. 36. Hughes JM, Kuiper EJ, Klaassen I, Canning P, Stitt AW, et al. (2007) Advanced glycation end products cause increased CCN family and extracellular matrix gene expression in the diabetic rodent retina. Diabetologia 50: 1089–1098. 37. Kuiper EJ, Witmer AN, Klaassen I, Oliver N, Goldschmeding R, et al. (2004) Differential expression of connective tissue growth factor in microglia and pericytes in the human diabetic retina. Br J Ophthalmol 88: 1082–1087. 38. Spaide RF, Fisher YL (2006) Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina 26: 275–278. 39. Mason JO 3rd, Nixon PA, White MF (2006) Intravitreal injection of bevacizumab (Avastin) as adjunctive treatment of proliferative diabetic retinopathy. Am J Ophthalmol 142: 685–688. 40. Avery RL, Pearlman J, Pieramici DJ, Rabena MD, Castellarin AA, et al. (2006) Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 113: 1695–1715. 41. Hashimoto G, Inoki I, Fujii Y, Aoki T, Ikeda E, et al. (2002) Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165. J Biol Chem 277: 36288–36295. 42. Chang CC, Lin MT, Lin BR, Jeng YM, Chen ST, et al. (2006) Effect of connective tissue growth factor on hypoxia-inducible factor 1alpha degradation and tumor angiogenesis. J Natl Cancer Inst 98: 984–995. 43. Yokoi H, Mukoyama M, Nagae T, Mori K, Suganami T, et al. (2004) Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis. J Am Soc Nephrol 15: 1430–1440. 44. Kita T, Hata Y, Miura M, Kawahara S, Nakao S, et al. (2007) Functional characteristics of connective tissue growth factor on vitreoretinal cells. Diabetes 56: 1421–1428. 45. Hoshijima M, Hattori T, Inoue M, Araki D, Hanagata H, et al. (2006) CT domain of CCN2/CTGF directly interacts with fibronectin and enhances cell adhesion of chondrocytes through integrin alpha5beta1. FEBS Lett 580: 1376–82. 46. Gao R, Brigstock DR (2005) A novel integrin alpha5beta1 binding domain in module 4 of connective tissue growth factor (CCN2/CTGF) promotes adhesion and migration of activated pancreatic stellate cells. Gut 55: 856–862. 47. Nishida T, Kubota S, Fukunaga T, Kondo S, Yosimichi G, et al. (2003) CTGF/ Hcs24, hypertrophic chondrocyte-specific gene product, interacts with perlecan in regulating the proliferation and differentiation of chondrocytes. J Cell Physiol 196: 265–275. 48. Frazier K, Williams S, Kothapalli D, Klapper H, Grotendorst GR (1996) Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor. J Invest Dermatol 107: 404–411. 49. Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, et al. (1999) Connective tissue growth factor mediates transforming growth factor beta- induced collagen synthesis: down-regulation by cAMP. FASEB J 13: 1774–1786. 50. Yokoi H, Sugawara A, Mukoyama M, Mori K, Makino H, et al. (2001) Role of connective tissue growth factor in profibrotic action of transforming growth factor-beta: a potential target for preventing renal fibrosis. Am J Kidney Dis 38: S134–138. 51. He S, Chen Y, Khankan R, Barron E, Burton R, et al. (2008) Connective tissue growth factor as a mediator of intraocular fibrosis. Invest Ophthalmol Vis Sci, april 30, in press. PLoS ONE | www.plosone.org 7 July 2008 | Volume 3 | Issue 7 | e2675