Journal of Cell Communication and Signaling

, Volume 7, Issue 4, pp 253–263 | Cite as

Cysteine-rich protein 61 (CCN1) and connective tissue growth factor (CCN2) at the crosshairs of ocular neovascular and fibrovascular disease therapy



The vasculature forms a highly branched network investing every organ of vertebrate organisms. The retinal circulation, in particular, is supported by a central retinal artery branching into superficial arteries, which dive into the retina to form a dense network of capillaries in the deeper retinal layers. The function of the retina is highly dependent on the integrity and proper functioning of its vascular network and numerous ocular diseases including diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity are caused by vascular abnormalities culminating in total and sometimes irreversible loss of vision. CCN1 and CCN2 are inducible extracellular matrix (ECM) proteins which play a major role in normal and aberrant formation of blood vessels as their expression is associated with developmental and pathological angiogenesis. Both CCN1 and CCN2 achieve disparate cell-type and context-dependent activities through modulation of the angiogenic and synthetic phenotype of vascular and mesenchymal cells respectively. At the molecular level, CCN1 and CCN2 may control capillary growth and vascular cell differentiation by altering the composition or function of the constitutive ECM proteins, potentiating or interfering with the activity of various ligands and/or their receptors, physically interfering with the ECM-cell surface interconnections, and/or reprogramming gene expression driving cells toward new phenotypes. As such, these proteins emerged as important prognostic markers and potential therapeutic targets in neovascular and fibrovascular diseases of the eye. The purpose of this review is to highlight our current knowledge and understanding of the most recent data linking CCN1 and CCN2 signaling to ocular neovascularization bolstering the potential value of targeting these proteins in a therapeutic context.


CCN1 CCN2 Extracellular matrix Neovascularization Retinopathy Ischemia 



Advanced glycation end-product


Age-related macular degeneration




Choroidal neovascularization


Extracellular matrix


Ganglion cell layer


Green fluorescent protein


Insulin-like growth factor


Inner plexiform layer


Inner nuclear layer


Matrix metalloproteinase


Oxygen-induced retinopathy


Proliferative diabetic retinopathy


Retinal pigment epithelium


Retinopathy of Prematurity


Reactive oxygen species


Transforming growth factor


Tumor necrosis growth factor


Vascular endothelial growth factor



This work was supported by grant from the National Eye Institute of the National Institutes of Health EY022091-01 and Research for the Prevention of Blindness Foundation.


  1. El Abd KT, Kubota S, Janune D, Nishida T, Hattori T, Aoyama E, Perbal B, Kuboki T, Takigawa M (2013) Anti-fibrotic effect of CCN3 accompanied by altered gene expression profile of the CCN family. J Cell Commun Signal 7:11–18CrossRefGoogle Scholar
  2. Aiello LP, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL III, Klein R (1998) Diabetic retinopathy. Diabetes Care 21:143–156PubMedGoogle Scholar
  3. Armstrong LC, Bornstein P (2003) Thrombospondins 1 and 2 function as inhibitors of angiogenesis. Matrix Biol 22:63–71PubMedCrossRefGoogle Scholar
  4. Arnott JA, Lambi AG, Mundy C, Hendesi H, Pixley RA, Owen TA, Safadi FF, Popoff SN (2011) The role of connective tissue growth factor (CTGF/CCN2) in skeletogenesis. Crit Rev Eukaryot Gene Expr 21:43–69PubMedCentralPubMedCrossRefGoogle Scholar
  5. 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 19:2958–2966PubMedCentralPubMedGoogle Scholar
  6. Bader BL, Rayburn H, Crowley D, Hynes RO (1998) Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell 95:507–519PubMedCrossRefGoogle Scholar
  7. Barzegar-Befroei N, Peto T, Bergen AA, Lengyel I (2012) Understanding the role of Bruch’s membrane in CNV. Retinal Physician 9:20–25Google Scholar
  8. Bornstein P, Sage EH (2002) Matricellular proteins: Extracellular modulators of cell function. Curr Opin Cell Biol 14:608–616PubMedCrossRefGoogle Scholar
  9. Bou-Gharios G, Ponticos M, Rajkumar V, Abraham D (2004) Extra-cellular matrix in vascular networks. Cell Prolif 37:207–220PubMedCrossRefGoogle Scholar
  10. Brigstock DR (2003) The CCN family: A new stimulus package. J Endocrinol 178:169–175PubMedCrossRefGoogle Scholar
  11. Bryant DM, Stow JL (2005) Nuclear translocation of cell-surface receptors: Lessons from fibroblast growth factor. Traffic 6:947–954PubMedCrossRefGoogle Scholar
  12. Caballero S, Yang R, Grant MB, Chaqour B (2011) Selective blockade of cytoskeletal actin remodeling reduces experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 52:2490–2496PubMedCentralPubMedCrossRefGoogle Scholar
  13. Campochiaro PA (2000) Retinal and choroidal neovascularization. J Cell Physiol 184:301–310PubMedCrossRefGoogle Scholar
  14. Caprara C, Grimm C (2012) From oxygen to erythropoietin: Relevance of hypoxia for retinal development, health and disease. Prog Retin Eye Res 31:89–119PubMedCrossRefGoogle Scholar
  15. Chen CC, Lau LF (2009) Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol 41:771–783PubMedCentralPubMedCrossRefGoogle Scholar
  16. Chen N, Leu SJ, Todorovic V, Lam SC, Lau LF (2004) Identification of a novel integrin alphavbeta3 binding site in CCN1 (CYR61) critical for pro-angiogenic activities in vascular endothelial cells. J Biol Chem 279:44166–44176PubMedCrossRefGoogle Scholar
  17. Chen Y, Du XY (2007) Functional properties and intracellular signaling of CCN1/Cyr61. J Cell Biochem 100:1337–1345PubMedCrossRefGoogle Scholar
  18. Chintala H, Liu H, Parmar R, Kamalska M, Kim YJ, Lovett D, Grant MB, Chaqour B (2012) Connective tissue growth factor regulates retinal neovascularization through p53 protein-dependent transactivation of the matrix metalloproteinase (MMP)-2 gene. J Biol Chem 287:40570–40585PubMedCentralPubMedCrossRefGoogle Scholar
  19. Chudgar SM, Deng P, Maddala R, Epstein DL, Rao PV (2006) Regulation of connective tissue growth factor expression in the aqueous humor outflow pathway. Mol Vis 12:1117–1126PubMedGoogle Scholar
  20. Dams I, Wasyluk J, Prost M, Kutner A (2013) Therapeutic uses of prostaglandin F(2alpha) analogues in ocular disease and novel synthetic strategies. Prostaglandins Other Lipid Mediat.Google Scholar
  21. Das A, McGuire PG (2003) Retinal and choroidal angiogenesis: Pathophysiology and strategies for inhibition. Prog Retin Eye Res 22:721–748PubMedCrossRefGoogle Scholar
  22. De S, Razorenova O, McCabe NP, O’Toole T, Qin J, Byzova TV (2005) VEGF-integrin interplay controls tumor growth and vascularization. Proc Natl Acad Sci U S A 102:7589–7594PubMedCentralPubMedCrossRefGoogle Scholar
  23. Doherty HE, Kim HS, Hiller S, Sulik KK, Maeda N (2010) A mouse strain where basal connective tissue growth factor gene expression can be switched from low to high. PLoS One 5:e12909PubMedCentralPubMedCrossRefGoogle Scholar
  24. Dulmovits BM, Herman IM (2012) Microvascular remodeling and wound healing: A role for pericytes. Int J Biochem Cell Biol 44:1800–1812PubMedCentralPubMedCrossRefGoogle Scholar
  25. Francischetti IM, Kotsyfakis M, Andersen JF, Lukszo J (2010) Cyr61/CCN1 Displays high-affinity binding to the somatomedin B(1–44) domain of vitronectin. PLoS One 5:e9356PubMedCentralPubMedCrossRefGoogle Scholar
  26. Fuchshofer R, Stephan DA, Russell P, Tamm ER (2009) Gene expression profiling of TGFbeta2- and/or BMP7-treated trabecular meshwork cells: Identification of Smad7 as a critical inhibitor of TGF-beta2 signaling. Exp Eye Res 88:1020–1032PubMedCentralPubMedCrossRefGoogle Scholar
  27. Gao R, Brigstock DR (2003) Low density lipoprotein receptor-related protein (LRP) is a heparin-dependent adhesion receptor for connective tissue growth factor (CTGF) in rat activated hepatic stellate cells. Hepatol Res 27:214–220PubMedCrossRefGoogle Scholar
  28. Geraldes P, Hiraoka-Yamamoto J, Matsumoto M, Clermont A, Leitges M, Marette A, Aiello LP, Kern TS, King GL (2009) Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat Med 15:1298–1306PubMedCentralPubMedCrossRefGoogle Scholar
  29. Hall-Glenn F, De Young RA, Huang BL, van Handel B, Hofmann JJ, Chen TT, Choi A, Ong JR, Benya PD, Mikkola H, Iruela-Arispe ML, Lyons KM (2012) CCN2/Connective tissue growth factor is essential for pericyte adhesion and endothelial basement membrane formation during angiogenesis. PLoS One 7:e30562PubMedCentralPubMedCrossRefGoogle Scholar
  30. Han JS, Macarak E, Rosenbloom J, Chung KC, Chaqour B (2003) Regulation of Cyr61/CCN1 gene expression through RhoA GTPase and p38MAPK signaling pathways. Eur J Biochem 270:3408–3421PubMedCrossRefGoogle Scholar
  31. Hanna M, Liu H, Amir J, Sun Y, Morris SW, Siddiqui MA, Lau LF, Chaqour B (2009) Mechanical regulation of the proangiogenic factor CCN1/CYR61 gene requires the combined activities of MRTF-A and CREB-binding protein histone acetyltransferase. J Biol Chem 284:23125–23136PubMedCentralPubMedCrossRefGoogle Scholar
  32. Hartnett ME, Penn JS (2012) Mechanisms and management of retinopathy of prematurity. N Engl J Med 367:2515–2526PubMedCentralPubMedCrossRefGoogle Scholar
  33. Hasan A, Pokeza N, Shaw L, Lee HS, Lazzaro D, Chintala H, Rosenbaum D, Grant MB, Chaqour B (2011) The matricellular protein cysteine-rich protein 61 (CCN1/Cyr61) enhances physiological adaptation of retinal vessels and reduces pathological neovascularization associated with ischemic retinopathy. J Biol Chem 286:9542–9554PubMedCentralPubMedCrossRefGoogle Scholar
  34. He S, Jin ML, Worpel V, Hinton DR (2003) A role for connective tissue growth factor in the pathogenesis of choroidal neovascularization. Arch Ophthalmol 121:1283–1288PubMedCrossRefGoogle Scholar
  35. Heath E, Tahri D, Andermarcher E, Schofield P, Fleming S, Boulter CA (2008) Abnormal skeletal and cardiac development, cardiomyopathy, muscle atrophy and cataracts in mice with a targeted disruption of the Nov (Ccn3) gene. BMC Dev Biol 8:18PubMedCentralPubMedCrossRefGoogle Scholar
  36. Heavner W, Pevny L (2012) Eye development and retinogenesis. Cold Spring Harb Perspect Biol 4Google Scholar
  37. Hendrickx M, Leyns L (2008) Non-conventional frizzled ligands and Wnt receptors. Dev Growth Differ 50:229–243PubMedCrossRefGoogle Scholar
  38. Hilfiker-Kleiner D, Kaminski K, Kaminska A, Fuchs M, Klein G, Podewski E, Grote K, Kiian I, Wollert KC, Hilfiker A, Drexler H (2004) Regulation of proangiogenic factor CCN1 in cardiac muscle: Impact of ischemia, pressure overload, and neurohumoral activation. Circulation 109:2227–2233PubMedCrossRefGoogle Scholar
  39. Hinton DR, Spee C, He S, Weitz S, Usinger W, LaBree L, Oliver N, Lim JI (2004) Accumulation of NH2-terminal fragment of connective tissue growth factor in the vitreous of patients with proliferative diabetic retinopathy. Diabetes Care 27:758–764PubMedCrossRefGoogle Scholar
  40. Hirschfeld M, zur Hausen A, Bettendorf H, Jager M, Stickeler E (2009) Alternative splicing of Cyr61 is regulated by hypoxia and significantly changed in breast cancer. Cancer Res 69:2082–2090PubMedCrossRefGoogle Scholar
  41. Holbourn KP, Perbal B, Ravi AK (2009) Proteins on the catwalk: Modelling the structural domains of the CCN family of proteins. J Cell Commun Signal 3:25–41PubMedCentralPubMedCrossRefGoogle Scholar
  42. Hughes JM, Kuiper EJ, Klaassen I, Canning P, Stitt AW, Van BJ, Schalkwijk CG, Van Noorden CJ, Schlingemann RO (2007) Advanced glycation end products cause increased CCN family and extracellular matrix gene expression in the diabetic rodent retina. Diabetologia 50:1089–1098PubMedCentralPubMedCrossRefGoogle Scholar
  43. Inoki I, Shiomi T, Hashimoto G, Enomoto H, Nakamura H, Makino K, Ikeda E, Takata S, Kobayashi K, Okada Y (2002) Connective tissue growth factor binds vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis. FASEB J 16:219–221PubMedGoogle Scholar
  44. Ishida S, Yamashiro K, Usui T, Kaji Y, Ogura Y, Hida T, Honda Y, Oguchi Y, Adamis AP (2003) Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease. Nat Med 9:781–788PubMedCrossRefGoogle Scholar
  45. Ivkovic S, Yoon BS, Popoff SN, Safadi FF, Libuda DE, Stephenson RC, Daluiski A, Lyons KM (2003) Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development 130:2779–2791PubMedCentralPubMedCrossRefGoogle Scholar
  46. Jans DA (1994) Nuclear signaling pathways for polypeptide ligands and their membrane receptors? FASEB J 8:841–847PubMedGoogle Scholar
  47. Jin Y, Kim HP, Ifedigbo E, Lau LF, Choi AM (2005) Cyr61 Protects against hyperoxia-induced cell death via Akt pathway in pulmonary epithelial cells. Am J Respir Cell Mol Biol 33:297–302PubMedCrossRefGoogle Scholar
  48. Jun JI, Lau LF (2011) Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat Rev Drug Discov 10:945–963PubMedCentralPubMedCrossRefGoogle Scholar
  49. Juric V, Chen CC, Lau LF (2012) TNFalpha-induced apoptosis enabled by CCN1/CYR61: Pathways of reactive oxygen species generation and cytochrome c release. PLoS One 7:e31303PubMedCentralPubMedCrossRefGoogle Scholar
  50. Kennedy L, Liu S, Shi-Wen X, Chen Y, Eastwood M, Sabetkar M, Carter DE, Lyons KM, Black CM, Abraham DJ, Leask A (2007) CCN2 Is necessary for the function of mouse embryonic fibroblasts. Exp Cell Res 313:952–964PubMedCrossRefGoogle Scholar
  51. Kim KH, Chen CC, Monzon RI, Lau LF (2013). The Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol Cell Biol.Google Scholar
  52. Kita T, Hata Y, Kano K, Miura M, Nakao S, Noda Y, Shimokawa H, Ishibashi T (2007) Transforming growth factor-beta2 and connective tissue growth factor in proliferative vitreoretinal diseases: Possible involvement of hyalocytes and therapeutic potential of Rho kinase inhibitor. Diabetes 56:231–238PubMedCrossRefGoogle Scholar
  53. Kuiper EJ, Van Nieuwenhoven FA, de Smet MD, van Meurs JC, Tanck MW, Oliver N, Klaassen I, Van Noorden CJ, Goldschmeding R, Schlingemann RO (2008a) The angio-fibrotic switch of VEGF and CTGF in proliferative diabetic retinopathy. PLoS One 3:e2675PubMedCentralPubMedCrossRefGoogle Scholar
  54. Kuiper EJ, van Zijderveld R, Roestenberg P, Lyons KM, Goldschmeding R, Klaassen I, Van Noorden CJ, Schlingemann RO (2008b) Connective tissue growth factor is necessary for retinal capillary basal lamina thickening in diabetic mice. J Histochem Cytochem 56:785–792PubMedCentralPubMedCrossRefGoogle Scholar
  55. Kwon YH, Fingert JH, Kuehn MH, Alward WL (2009) Primary open-angle glaucoma. N Engl J Med 360:1113–1124PubMedCentralPubMedCrossRefGoogle Scholar
  56. Leask A, Abraham DJ (2006) All in the CCN family: Essential matricellular signaling modulators emerge from the bunker. J Cell Sci 119:4803–4810PubMedCrossRefGoogle Scholar
  57. Lee HY, Chung JW, Youn SW, Kim JY, Park KW, Koo BK, Oh BH, Park YB, Chaqour B, Walsh K, Kim HS (2007) Forkhead transcription factor FOXO3a is a negative regulator of angiogenic immediate early gene CYR61, leading to inhibition of vascular smooth muscle cell proliferation and neointimal hyperplasia. Circ Res 100:372–380PubMedCrossRefGoogle Scholar
  58. Li SY, Fu ZJ, Lo AC (2012) Hypoxia-induced oxidative stress in ischemic retinopathy. Oxid Med Cell Longev 2012:426769PubMedCentralPubMedGoogle Scholar
  59. Liang Y, Li C, Guzman VM, Evinger AJ III, Protzman CE, Krauss AH, Woodward DF (2003) Comparison of prostaglandin F2alpha, bimatoprost (prostamide), and butaprost (EP2 agonist) on Cyr61 and connective tissue growth factor gene expression. J Biol Chem 278:27267–27277PubMedCrossRefGoogle Scholar
  60. Liu H, Yang R, Tinner B, Choudhry A, Schutze N, Chaqour B (2008) Cysteine-rich protein 61 and connective tissue growth factor induce deadhesion and anoikis of retinal pericytes. Endocrinology 149:1666–1677PubMedCrossRefGoogle Scholar
  61. Lutty GA, Hasegawa T, Baba T, Grebe R, Bhutto I, McLeod DS (2010) Development of the human choriocapillaris. Eye (Lond) 24:408–415CrossRefGoogle Scholar
  62. Martinez-Castellanos MA, Schwartz S, Hernandez-Rojas ML, Kon-Jara VA, Garcia-Aguirre G, Guerrero-Naranjo JL, Chan RV, Quiroz-Mercado H (2013) Long-term effect of antiangiogenic therapy for retinopathy of prematurity up to 5 years of follow-up. Retina 33:329–338PubMedCrossRefGoogle Scholar
  63. Mason RM (2009) Connective tissue growth factor(CCN2), a pathogenic factor in diabetic nephropathy. What does it do? How does it do it? J Cell Commun Signal 3:95–104PubMedCentralPubMedCrossRefGoogle Scholar
  64. Mintz-Hittner HA (2012) Treatment of retinopathy of prematurity with vascular endothelial growth factor inhibitors. Early Hum Dev 88:937–941PubMedCrossRefGoogle Scholar
  65. Mo FE, Lau LF (2006) The matricellular protein CCN1 is essential for cardiac development. Circ Res 99:961–969PubMedCentralPubMedCrossRefGoogle Scholar
  66. Mo FE, Muntean AG, Chen CC, Stolz DB, Watkins SC, Lau LF (2002) CYR61 (CCN1) Is essential for placental development and vascular integrity. Mol Cell Biol 22:8709–8720PubMedCentralPubMedCrossRefGoogle Scholar
  67. Nakamura-Ishizu A, Kurihara T, Okuno Y, Ozawa Y, Kishi K, Goda N, Tsubota K, Okano H, Suda T, Kubota Y (2012) The formation of an angiogenic astrocyte template is regulated by the neuroretina in a HIF-1-dependent manner. Dev Biol 363:106–114PubMedCrossRefGoogle Scholar
  68. Neelam K, Cheung CM, Ohno-Matsui K, Lai TY, Wong TY (2012) Choroidal neovascularization in pathological myopia. Prog Retin Eye Res 31:495–525PubMedCrossRefGoogle Scholar
  69. Perbal B (2013) CCN proteins: A centralized communication network. J Cell Commun Signal. doi: 10.1007/s12079-013-0193-7 Google Scholar
  70. Perkowski S, Sun J, Singhal S, Santiago J, Leikauf GD, Albelda SM (2003) Gene expression profiling of the early pulmonary response to hyperoxia in mice. Am J Respir Cell Mol Biol 28:682–696PubMedCrossRefGoogle Scholar
  71. Planque N, Long LC, Saule S, Bleau AM, Perbal B (2006) Nuclear addressing provides a clue for the transforming activity of amino-truncated CCN3 proteins. J Cell Biochem 99:105–116PubMedCrossRefGoogle Scholar
  72. Provis JM (2001) Development of the primate retinal vasculature. Prog Retin Eye Res 20:799–821PubMedCrossRefGoogle Scholar
  73. Quigley HA (2011) Glaucoma. Lancet 377:1367–1377PubMedCrossRefGoogle Scholar
  74. Saint-Geniez M, D’Amore PA (2004) Development and pathology of the hyaloid, choroidal and retinal vasculature. Int J Dev Biol 48:1045–1058PubMedCrossRefGoogle Scholar
  75. Schober JM, Chen N, Grzeszkiewicz TM, Jovanovic I, Emeson EE, Ugarova TP, Ye RD, Lau LF, Lam SC (2002) Identification of integrin alpha(M)beta(2) as an adhesion receptor on peripheral blood monocytes for Cyr61 (CCN1) and connective tissue growth factor (CCN2): immediate-early gene products expressed in atherosclerotic lesions. Blood 99:4457–4465PubMedCrossRefGoogle Scholar
  76. Schwartz K, Budenz D (2004) Current management of glaucoma. Curr Opin Ophthalmol 15:119–126PubMedCrossRefGoogle Scholar
  77. Segarini PR, Nesbitt JE, Li D, Hays LG, Yates JR III, Carmichael DF (2001) The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor is a receptor for connective tissue growth factor. J Biol Chem 276:40659–40667PubMedCrossRefGoogle Scholar
  78. Shimo T, Nakanishi T, Nishida T, Asano M, Kanyama M, Kuboki T, Tamatani T, Tezuka K, Takemura M, Matsumura T, Takigawa M (1999) Connective tissue growth factor induces the proliferation, migration, and tube formation of vascular endothelial cells in vitro, and angiogenesis in vivo. J Biochem 126:137–145PubMedCrossRefGoogle Scholar
  79. Shimoyama T, Hiraoka S, Takemoto M, Koshizaka M, Tokuyama H, Tokuyama T, Watanabe A, Fujimoto M, Kawamura H, Sato S, Tsurutani Y, Saito Y, Perbal B, Koseki H, Yokote K (2010) CCN3 Inhibits neointimal hyperplasia through modulation of smooth muscle cell growth and migration. Arterioscler Thromb Vasc Biol 30:675–682PubMedCrossRefGoogle Scholar
  80. Si W, Kang Q, Luu HH, Park JK, Luo Q, Song WX, Jiang W, Luo X, Li X, Yin H, Montag AG, Haydon RC, He TC (2006) CCN1/Cyr61 Is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells. Mol Cell Biol 26:2955–2964PubMedCentralPubMedCrossRefGoogle Scholar
  81. Stalmans I (2005) Role of the vascular endothelial growth factor isoforms in retinal angiogenesis and DiGeorge syndrome. Verh K Acad Geneeskd Belg 67:229–276PubMedGoogle Scholar
  82. Tamm ER (2009) The trabecular meshwork outflow pathways: Structural and functional aspects. Exp Eye Res 88:648–655PubMedCrossRefGoogle Scholar
  83. Tamura I, Rosenbloom J, Macarak E, Chaqour B (2001) Regulation of Cyr61 gene expression by mechanical stretch through multiple signaling pathways. Am J Physiol Cell Physiol 281:C1524–C1532PubMedGoogle Scholar
  84. Twigg SM, Chen MM, Joly AH, Chakrapani SD, Tsubaki J, Kim HS, Oh Y, Rosenfeld RG (2001) Advanced glycosylation end products up-regulate connective tissue growth factor (insulin-like growth factor-binding protein-related protein 2) in human fibroblasts: A potential mechanism for expansion of extracellular matrix in diabetes mellitus. Endocrinology 142:1760–1769PubMedCrossRefGoogle Scholar
  85. Van Geest RJ, Klaassen I, Lesnik-Oberstein SY, Tan HS, Mura M, Goldschmeding R, Van Noorden CJ, Schlingemann RO (2013) Vitreous TIMP-1 levels associate with neovascularization and TGF-beta2 levels but not with fibrosis in the clinical course of proliferative diabetic retinopathy. J Cell Commun Signal 7:1–9PubMedCentralPubMedCrossRefGoogle Scholar
  86. Vogel V (2006) Mechanotransduction involving multimodular proteins: Converting force into biochemical signals. Annu Rev Biophys Biomol Struct 35:459–488PubMedCrossRefGoogle Scholar
  87. Wahab NA, Brinkman H, Mason RM (2001) Uptake and intracellular transport of the connective tissue growth factor: A potential mode of action. Biochem J 359:89–97PubMedCentralPubMedCrossRefGoogle Scholar
  88. Warden SM, Andreoli CM, Mukai S (2007) The Wnt signaling pathway in familial exudative vitreoretinopathy and norrie disease. Semin Ophthalmol 22:211–217PubMedCrossRefGoogle Scholar
  89. 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 25:911–918PubMedCrossRefGoogle Scholar
  90. Workman G, Sage EH (2011) Identification of a sequence in the matricellular protein SPARC that interacts with the scavenger receptor stabilin-1. J Cell Biochem 112:1003–1008PubMedCrossRefGoogle Scholar
  91. Yang R, Liu H, Williams I, Chaqour B (2007) Matrix metalloproteinase-2 expression and apoptogenic activity in retinal pericytes: Implications in diabetic retinopathy. Ann N Y Acad Sci 1103:196–201PubMedCrossRefGoogle Scholar
  92. Zhu M, Madigan MC, van Driel D, Maslim J, Billson FA, Provis JM, Penfold PL (2000) The human hyaloid system: Cell death and vascular regression. Exp Eye Res 70:767–776PubMedCrossRefGoogle Scholar

Copyright information

© The International CCN Society 2013

Authors and Affiliations

  1. 1.Department of Cell Biology and Department of OphthalmologyState University of New York (SUNY) Eye Institute Downstate Medical CenterBrooklynUSA

Personalised recommendations