[en] Connective tissue growth factor (CTGF) is a member of the CCN family of growth factors. CTGF is important in scarring, wound healing, and fibrosis. It has also been implicated to play a role in angiogenesis, in addition to vascular endothelial growth factor (VEGF). In the eye, angiogenesis and subsequent fibrosis are the main causes of blindness in conditions such as diabetic retinopathy. We have applied three different models of angiogenesis to homozygous CTGF(-/-) and heterozygous CTGF(+/-) mice to establish involvement of CTGF in neovascularization. CTGF(+/-) mice die around birth. Therefore, embryonic CTGF(-/-), CTGF(-/-), and CTGF(+/+) bone explants were used to study in vitro angiogenesis, and neonatal and mature CTGF(+/-) and CTGF(+/+) mice were used in models of oxygen-induced retinopathy and laser-induced choroidal neovascularization. Angiogenesis in vitro was independent of the CTGF genotype in both the presence and the absence of VEGF. Oxygen-induced vascular pathology in the retina, as determined semi-quantitatively, and laser-induced choroidal neovascularization, as determined quantitatively, were also not affected by the CTGF genotype. Our data show that downregulation of CTGF levels does not affect neovascularization, indicating distinct roles of VEGF and CTGF in angiogenesis and fibrosis in eye conditions.
Disciplines :
Ophthalmology
Author, co-author :
Kuiper, Esther J.
Roestenberg, Peggy
Ehlken, Christoph
Lambert, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > Ophtalmologie
van Treslong-de Groot, Henny Bloys
Lyons, Karen M.
Agostini, Hans-Jürgen T.
Rakic, Jean-Marie ; Université de Liège - ULiège > Département des sciences cliniques > Ophtalmologie
Klaassen, Ingeborg
Van Noorden, Cornelis J. F.
Goldschmeding, Roel
Schlingemann, Reinier O.
Language :
English
Title :
Angiogenesis is not impaired in connective tissue growth factor (CTGF) knock-out mice
Publication date :
November 2007
Journal title :
Journal of Histochemistry and Cytochemistry
ISSN :
0022-1554
eISSN :
1551-5044
Publisher :
Histochemical Soc Inc, Seattle, United States - Washington
Agostini H, Boden K, Unsold A, Martin G, Hansen L, Fiedler U, Esser N, et al. (2005) A single local injection of recombinant VEGF receptor 2 but not of Tie2 inhibits retinal neovascularization in the mouse. Curr Eye Res 30:249-257
Aiello LP, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL, Klein R (1998) Diabetic retinopathy. Diabetes Care 21:143-156
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
Campochiaro PA, Hackett SF (2003) Ocular neovascularization: a valuable model system. Oncogene 22:6537-6548
Chang CC, Lin MT, Lin BR, Jeng YM, Chen ST, Chu CY, Chen RJ, et al. (2006) Effect of connective tissue growth factor on hypoxia-inducible factor la degradation and tumor angiogenesis. J Natl Cancer Inst 98:984-995
Deckers M, van der Pluijm G, Dooijewaard S, Kroon M, van Hinsbergh V, Papapoulos S, Löwik C (2001) Effect of angiogenic and antiangiogenic compounds on the outgrowth of capillary structures from fetal mouse bone explants. Lab Invest 81:5-15
Ferrara N (1999a) Vascular endothelial growth factor: molecular and biological aspects. Curr Top Microbiol Immunol 237:1-30
Ferrara N (1999b) Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int 56:794-814
Franklin TJ (1997) Therapeutic approaches to organ fibrosis. Int J Biochem Cell Biol 29:79-89
Goldschmeding R, Aten J, Ito Y, Blom I, Rabelink T, Weening JJ (2000) Connective tissue growth factor: just another factor in renal fibrosis? Nephrol Dial Transplant 15:296-299
Grotendorst GR (1997) Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev 8:171-179
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
Higgins DF, Biju MP, Akai Y, Wutz A, Johnson RS, Haase VH (2004) Hypoxic induction of Ctgf is directly mediated by Hif-1. Am J Physiol Renal Physiol 287:F1223-F1232
Higgins RD, Yu K, Sanders RJ, Nandgaonkar BN, Rotschild T, Rifkin DB (1999) Diltiazem reduces retinal neovascularization in a mouse model of oxygen induced retinopathy. Curr Eye Res 18:20-27
Hinton DR, Spee C, He S, Weitz S, Usinger W, LaBree L, Oliver N, 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
Hughes JM, Kuiper EJ, Klaassen I, Canning P, Stitt AW, Van Bezu J, Schalkwijk CG, 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
Inoki I, Shiomi T, Hashimoto G, Enomoto H, Nakamura H, Makino K, Ikeda E, et al. (2002) Connective tissue growth factor binds vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis. FASEBJ 16:219-221
Ivkovic S, Yoon BS, Popoff SN, Safadi FF, Libuda DE, Stephenson RC, Daluiski A, et al. (2003) Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development 130:2779-2791
Jang HS, Kim HJ, Kim JM, Lee YS, Kim KL, Kim JA, Lee JY, 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
Kuiper EJ (2006) The Role of CTGF in Diabetic Retinopathy. PhD Thesis. University of Amsterdam, Amsterdam, The Netherlands
Kuiper EJ, De Smet MD, Van Meurs JC, Tan HS, Tanck MWT, Oliver N, Van Nieuwenhoven FA, et al. (2006) Association of connective tissue growth factor with fibrosis in vitreoretinal disorders. Arch Ophthalmol 124:1457-1462
Kuiper EJ, Witmer AN, Klaassen I, Oliver N, Goldschmeding R, Schlingemann RO (2004) Differential expression of connective tissue growth factor in microglia and pericytes in the human diabetic retina. Br J Ophthalmol 88:1082-1087
Lambert V, Munaut C, Carmeliet P, Gerard RD, Declerck PJ, Gils A, Claes C, et al. (2003) Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type I: implications for clinical trials. Invest Ophthalmol Vis Sci 44:2791-2797
Lambert V, Munaut C, Noel A, Frankenne F, Bajou K, Gerard R, Carmeliet P, et al. (2001) Influence of plasminogen activator inhibitor type 1 on choroidal neovascularization. FASEB J 15:1021-1027
Mageto Y, Flaherty K, Brwon K, Fong A, Raghu G (2004) Safety and tolerability of human monoclonal antibody FG-3019, anticonnective tissue growth factor, in patients with idiopathic pulmonary fibrosis. Chest 126:773S
Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, Igarashi A, Takigawa M, 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
Perbal B (2004) CCN proteins: multifunctional signalling regulators. Lancet 363:62-64
Roestenberg P (2007) The Role of CTGF in Diabetic Nephropathy. PhD Thesis. University of Utrecht, Utrecht, The Netherlands
Shimo T, Nakanishi T, Nishida T, Asano M, Kanyama M, Kuboki T, Tamatani T, 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 (Tokyo) 126:137-145
Slieker WA, De Rijk-De Bruin MF, Leenen PJ, Van Ewijk W (1993) ER-MP12 antigen, a new cell surface marker on mouse bone marrow cells with thymus-repopulating ability: I. Intrathymic repopulating ability of ER-MP12-positive bone marrow cells. Int Immunol 5:1093-1098
Smith EK, Price DK, Figg WD (2006) Piecing together the HIF-1 puzzle: the role of the CTGF as a molecular mechanism of HIF-1 regulation. Cancer Biol Ther 5:1443-1444
Suzuma K, Naruse K, Suzuma I, Takahara N, Ueki K, Aiello LP, King GL (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
Tosetti F, Noonan DM, Albini A (2006) Choking hypoxia-inducible factor 1α: a novel mechanism for connective tissue growth factor inhibition of angiogenesis. J Natl Cancer Inst 98:946-948
Van der Pluijm G, Deckers M, Sijmons B, de Groot H, Bird J, Wills R, Papapoulos S, et al. (2003) In vitro and in vivo endochondral bone formation models allow identification of anti-angiogenic compounds. Am J Pathol 163:157-163
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
Watanabe D, Takagi H, Suzuma K, Oh H, Ohashi H, Honda Y (2005) Expression of connective tissue growth factor and its potential role in choroidal neovascularization. Retina 25:911-918
Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO (2003) Vascular endothelial growth factors and angiogenesis in eye disease. Prog Ret Eye Res 22:1-29
Yokoi H, Mukoyama M, Nagae T, Mori K, Suganami T, Sawai K, Yoshioka T, et al. (2004) Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis. J Am Soc Nephrol 15:1430-1440
Yokoi H, Sugawara A, Mukoyama M, Mori K, Makino H, Suganami T, Nagae T, 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 38:134-138
Yossuck P, Yan Y, Tadesse M, Higgins RD (2000) Dexamethasone and critical effect of timing on retinopathy. Invest Ophthalmol Vis Sci 41-3095-3099
