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ISRN Rheumatology
Volume 2013 (2013), Article ID 835948, 15 pages
http://dx.doi.org/10.1155/2013/835948
Review Article

Role of Endothelial to Mesenchymal Transition in the Pathogenesis of the Vascular Alterations in Systemic Sclerosis

1Jefferson Institute of Molecular Medicine, Philadelphia, PA 19107, USA
2Scleroderma Center, Thomas Jefferson University, Philadelphia, PA 19107, USA

Received 14 July 2013; Accepted 9 August 2013

Academic Editors: S. Bombardieri, H. Ihn, and T. Yamamoto

Copyright © 2013 Sergio A. Jimenez. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. Gabrielli, E. V. Avvedimento, and T. Krieg, “Scleroderma,” The New England Journal of Medicine, vol. 360, no. 19, pp. 1989–2003, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. S. A. Jimenez and C. T. Derk, “Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis,” Annals of Internal Medicine, vol. 140, no. 1, pp. 37–50, 2004. View at Scopus
  3. J. Varga and D. Abraham, “Systemic sclerosis: a prototypic multisystem fibrotic disorder,” Journal of Clinical Investigation, vol. 117, no. 3, pp. 557–567, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. T. R. Katsumoto, M. L. Whitfield, and M. K. Connolly, “The pathogenesis of systemic sclerosis,” Annual Review of Pathology: Mechanisms of Disease, vol. 6, pp. 509–537, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. C. P. Denton, C. M. Black, and D. J. Abraham, “Mechanisms and consequences of fibrosis in systemic sclerosis,” Nature Clinical Practice Rheumatology, vol. 2, pp. 134–144, 2006.
  6. T. A. Wynn, “Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases,” Journal of Clinical Investigation, vol. 117, no. 3, pp. 524–529, 2007. View at Publisher · View at Google Scholar · View at Scopus
  7. J. A. Varga and M. Trojanowska, “Fibrosis in systemic sclerosis,” Rheumatic Disease Clinics of North America, vol. 34, no. 1, pp. 115–143, 2008. View at Publisher · View at Google Scholar · View at Scopus
  8. M. Matucci-Cerinic, B. Kahaleh, and F. M. Wigley, “Systemic sclerosis, (scleroderma, SSc) is a vascular disease,” Arthritis and Rheumatism, vol. 65, no. 8, pp. 1953–1962, 2013. View at Publisher · View at Google Scholar
  9. B. Kahaleh, “Vascular disease in scleroderma: mechanisms of vascular injury,” Rheumatic Disease Clinics of North America, vol. 34, no. 1, pp. 57–71, 2008. View at Publisher · View at Google Scholar · View at Scopus
  10. M. Trojanowska, “Cellular and molecular aspects of vascular dysfunction in systemic sclerosis,” Nature Reviews Rheumatology, vol. 6, no. 8, pp. 453–460, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. T. A. Wynn and T. R. Ramalingam, “Mechanisms of fibrosis: therapeutic translation for fibrotic disease,” Nature Medicine, vol. 18, pp. 1028–1040, 2012. View at Publisher · View at Google Scholar
  12. T. Krieg, D. Abraham, and R. Lafyatis, “Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions,” Arthritis Research and Therapy, vol. 9, supplement 2, article S4, 2007. View at Publisher · View at Google Scholar · View at Scopus
  13. D. J. Abraham, B. Eckes, V. Rajkumar, and T. Krieg, “New developments in fibroblast and myofibroblast biology: implications for fibrosis and scleroderma,” Current Rheumatology Reports, vol. 9, no. 2, pp. 136–143, 2007. View at Publisher · View at Google Scholar · View at Scopus
  14. T. Z. Kirk, M. E. Mark, C. C. Chua, B. H. Chua, and M. D. Mayes, “Myofibroblasts from scleroderma skin synthesize elevated levels of collagen and tissue inhibitor of metalloproteinase (TIMP-1) with two forms of TIMP-1,” The Journal of Biological Chemistry, vol. 270, no. 7, pp. 3423–3428, 1995. View at Publisher · View at Google Scholar · View at Scopus
  15. E. Romano, M. Manetti, S. Guiducci, C. Ceccarelli, Y. Allanore, and M. Matucci-Cerinic, “The genetics of systemic sclerosis: an update,” Clinical and Experimental Rheumatology, vol. 29, no. 2, pp. S75–S86, 2011. View at Scopus
  16. M. D. Mayes, “The genetics of scleroderma: looking into the postgenomic era,” Current Opinion in Rheumatology, vol. 24, no. 6, pp. 677–684, 2012. View at Publisher · View at Google Scholar
  17. J. C. A. Broen, M. J. H. Coenen, and T. R. D. J. Radstake, “Genetics of systemic sclerosis: an update,” Current Rheumatology Reports, vol. 14, no. 1, pp. 11–21, 2012. View at Publisher · View at Google Scholar · View at Scopus
  18. J. E. Martín, L. Bossini-Castillo, and J. Martín, “Unraveling the genetic component of systemic sclerosis,” Human Genetics, vol. 131, no. 7, pp. 1023–1037, 2012. View at Publisher · View at Google Scholar
  19. C. Chizzolini, N. C. Brembilla, E. Montanari, and M. Truchetet, “Fibrosis and immune dysregulation in systemic sclerosis,” Autoimmunity Reviews, vol. 10, no. 5, pp. 276–281, 2011. View at Publisher · View at Google Scholar · View at Scopus
  20. Y. S. Gu, J. Kong, G. S. Cheema, C. L. Keen, G. Wick, and M. E. Gershwin, “The immunobiology of systemic sclerosis,” Seminars in Arthritis and Rheumatism, vol. 38, no. 2, pp. 132–160, 2008. View at Publisher · View at Google Scholar · View at Scopus
  21. M. R. York, “Novel insights on the role of the innate immune system in systemic sclerosis,” Expert Review of Clinical Immunology, vol. 7, no. 4, pp. 481–489, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. T. A. Wynn, “Cellular and molecular mechanisms of fibrosis,” Journal of Pathology, vol. 214, no. 2, pp. 199–210, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. V. Steen, C. P. Denton, J. E. Pope, and M. Matucci-Cerinic, “Digital ulcers: overt vascular disease in systemic sclerosis,” Rheumatology, vol. 48, supplement 3, pp. iii19–iii24, 2009. View at Scopus
  24. A. L. Herrick, “The pathogenesis, diagnosis and treatment of Raynaud phenomenon,” Nature Reviews Rheumatology, vol. 8, pp. 469–479, 2012. View at Publisher · View at Google Scholar
  25. V. D. Steen, “Scleroderma renal crisis,” Rheumatic Disease Clinics of North America, vol. 29, no. 2, pp. 315–333, 2003. View at Scopus
  26. L. Mouthon, A. Bérezné, G. Bussone, L. Noël, P. M. Villiger, and L. Guillevin, “Scleroderma renal crisis: a rare but severe complication of systemic sclerosis,” Clinical Reviews in Allergy and Immunology, vol. 40, no. 2, pp. 84–91, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. C. P. Denton and C. M. Black, “Pulmonary hypertension in systemic sclerosis,” Rheumatic Disease Clinics of North America, vol. 29, no. 2, pp. 335–349, 2003. View at Scopus
  28. A. Ramirez and J. Varga, “Pulmonary arterial hypertension in systematic sclerosis: clinical manifestations, pathophysiology, evaluation, and management,” Treatments in Respiratory Medicine, vol. 3, no. 6, pp. 339–352, 2004. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Chatterjee, “Pulmonary hypertension in systemic sclerosis,” Seminars in Arthritis and Rheumatism, vol. 41, no. 1, pp. 19–37, 2011. View at Publisher · View at Google Scholar · View at Scopus
  30. M. Cutolo, A. Sulli, and V. Smith, “Assessing microvascular changes in systemic sclerosis diagnosis and management,” Nature Reviews Rheumatology, vol. 6, no. 10, pp. 578–587, 2010. View at Publisher · View at Google Scholar · View at Scopus
  31. W. Grassi, P. D. Medico, F. Izzo, and C. Cervini, “Microvascular involvement in systemic sclerosis: capillaroscopic findings,” Seminars in Arthritis and Rheumatism, vol. 30, no. 6, pp. 397–402, 2001. View at Publisher · View at Google Scholar · View at Scopus
  32. A. A. Shah, F. M. Wigley, and L. K. Hummers, “Telangiectases in scleroderma: a potential clinical marker of pulmonary arterial hypertension,” Journal of Rheumatology, vol. 37, no. 1, pp. 98–104, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. M. M. El-Omar, A. P. Jenkins, K. Hollowood, A. K. Banerjee, and R. P. H. Thompson, “Gastric telangiectasis: a rare cause of severe blood loss in CREST syndrome,” Postgraduate Medical Journal, vol. 70, no. 822, pp. 302–304, 1994. View at Scopus
  34. B. Jharap, L. G. Koudstaal, E. A. Neefjes-Borst, and S. J. B. van Weyenberg, “Colonic telangiectasias in progressive systemic sclerosis,” Endoscopy, vol. 44, supplement 2, pp. E42–E43, 2012. View at Publisher · View at Google Scholar · View at Scopus
  35. E. V. Lally and S. A. Jimenez, “Impotence in progressive systemic sclerosis,” Annals of Internal Medicine, vol. 95, no. 2, pp. 150–153, 1981. View at Scopus
  36. S. Sukenik, J. Horowitz, D. Buskila, J. M. Abarbanel, L. Lismer, and I. Avinoach, “Impotence in systemic sclerosis,” Annals of Internal Medicine, vol. 106, no. 6, pp. 910–911, 1987. View at Scopus
  37. C. Foocharoen, A. Tyndall, E. Hachulla et al., “Erectile dysfunction is frequent in systemic sclerosis and associated with severe disease: a study of the EULAR scleroderma trial and research group,” Arthritis Research and Therapy, vol. 14, no. 1, article R37, 2012. View at Publisher · View at Google Scholar · View at Scopus
  38. C. T. Derk and S. A. Jimenez, “Acute myocardial infarction in systemic sclerosis patients: a case series,” Clinical Rheumatology, vol. 26, no. 6, pp. 965–968, 2007. View at Publisher · View at Google Scholar · View at Scopus
  39. Y. Allanore and C. Meune, “Primary myocardial involvement in systemic sclerosis: evidence for a microvascular origin,” Clinical and Experimental Rheumatology, vol. 28, no. 5, pp. S48–S53, 2010. View at Scopus
  40. M. Watson, R. J. Hally, P. A. McCue, J. Varga, and S. A. Jiménez, “Gastric antral vascular ectasia (watermelon stomach) in patients with systemic sclerosis,” Arthritis and Rheumatism, vol. 39, no. 2, pp. 341–346, 1996. View at Publisher · View at Google Scholar · View at Scopus
  41. K. M. Ingraham, M. S. O'Brien, M. A. X. Shenin, C. T. Derk, and V. D. Steen, “Gastric antral vascular ectasia in systemic sclerosis: demographics and disease predictors,” Journal of Rheumatology, vol. 37, no. 3, pp. 603–607, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. E. W. Hung, M. D. Mayes, R. Sharif, S. Assassi, V. I. Machicao, and C. Hosing, “Gastric antral vascular ectasia and its clinical correlates in patients with early diffuse systemic sclerosis in the SCOT trial,” Journal of Rheumatology, vol. 40, no. 4, pp. 455–460, 2013. View at Publisher · View at Google Scholar
  43. J. Busquets, Y. Lee, L. Santamarina et al., “Acute retinal artery occlusion in systemic sclerosis: a rare manifestation of systemic sclerosis fibroproliferative vasculopathy,” Seminars in Arthritis and Rheumatism, 2013. View at Publisher · View at Google Scholar
  44. M. Minasian, M. Stanford, E. Graham, C. P. Denton, and C. Black, “Bilateral ischaemic retinal vasculopathy in scleroderma,” The British Journal of Ophthalmology, vol. 89, no. 8, pp. 1064–1065, 2005. View at Publisher · View at Google Scholar · View at Scopus
  45. M. H. Taylor, J. A. McFadden, M. B. Bolster, and R. M. Silver, “Ulnar artery involvement in systemic sclerosis (scleroderma),” Journal of Rheumatology, vol. 29, no. 1, pp. 102–106, 2002. View at Scopus
  46. P. Youssef, H. Englert, and J. Bertouch, “Large vessel occlusive disease associated with CREST syndrome and scleroderma,” Annals of the Rheumatic Diseases, vol. 52, no. 6, pp. 464–466, 1993. View at Scopus
  47. U. Müller-Ladner, O. Distler, L. Ibba-Manneschi, E. Neumann, and S. Gay, “Mechanisms of vascular damage in systemic sclerosis,” Autoimmunity, vol. 42, no. 7, pp. 587–595, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. D. Abraham and O. Distler, “How does endothelial cell injury start? The role of endothelin in systemic sclerosis,” Arthritis Research and Therapy, vol. 9, supplement 2, article S2, 2007. View at Publisher · View at Google Scholar · View at Scopus
  49. J. P. Pandey and E. C. LeRoy, “Human cytomegalovirus and the vasculopathies of autoimmune diseases (especially scleroderma), allograft rejection, and coronary restenosis,” Arthritis and Rheumatism, vol. 41, no. 1, pp. 10–15, 1998.
  50. M. Neidhart, S. Kuchen, O. Distler et al., “Increased serum levels of antibodies against human cytomegalovirus and prevalence of autoantibodies in systemic sclerosis,” Arthritis and Rheumatism, vol. 42, pp. 389–392, 1999.
  51. Y. Renaudineau, R. Revelen, Y. Levy et al., “Anti-endothelial cell antibodies in systemic sclerosis,” Clinical and Diagnostic Laboratory Immunology, vol. 6, no. 2, pp. 156–160, 1999. View at Scopus
  52. F. Drenk and H. R. G. Deicher, “Pathophysiological effects of endothelial cytotoxic activity derived from sera of patients with progressive systemic sclerosis,” Journal of Rheumatology, vol. 15, no. 3, pp. 468–474, 1988. View at Scopus
  53. N. Del Papa, G. Colombo, N. Fracchiolla et al., “Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis,” Arthritis and Rheumatism, vol. 50, no. 4, pp. 1296–1304, 2004. View at Publisher · View at Google Scholar · View at Scopus
  54. J. Avouac, F. Juin, J. Wipff et al., “Circulating endothelial progenitor cells in systemic sclerosis: association with disease severity,” Annals of the Rheumatic Diseases, vol. 67, no. 10, pp. 1455–1460, 2008. View at Publisher · View at Google Scholar · View at Scopus
  55. Y. Allanore, F. Batteux, J. Avouac, N. Assous, B. Weill, and A. Kahan, “Levels of circulating endothelial progenitor cells in systemic sclerosis,” Clinical and Experimental Rheumatology, vol. 25, no. 1, pp. 60–66, 2007. View at Scopus
  56. A. Kuryliszyn-Moskal, P. A. Klimiuk, and S. Sierakowski, “Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement,” Clinical Rheumatology, vol. 24, no. 2, pp. 111–116, 2005. View at Publisher · View at Google Scholar · View at Scopus
  57. G. N. Andersen, K. Caidahl, E. Kazzam et al., “Correlation between increased nitric oxide production and markers of endothelial activation in systemic sclerosis: findings with the soluble adhesion molecules E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1,” Arthritis and Rheumatism, vol. 43, no. 5, pp. 1085–1093, 2000.
  58. M. J. Mulligan-Kehoe and M. Simons, “Vascular disease in scleroderma: angiogenesis and vascular repair,” Rheumatic Disease Clinics of North America, vol. 34, no. 1, pp. 73–79, 2008. View at Publisher · View at Google Scholar · View at Scopus
  59. M. M. Cerinic, G. Valentini, G. G. Sorano et al., “Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis,” Seminars in Arthritis and Rheumatism, vol. 32, no. 5, pp. 285–295, 2003. View at Publisher · View at Google Scholar · View at Scopus
  60. K. R. Stenmark, K. A. Fagan, and M. G. Frid, “Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms,” Circulation Research, vol. 99, no. 7, pp. 675–691, 2006. View at Publisher · View at Google Scholar · View at Scopus
  61. C. Beyer, G. Schett, S. Gay, O. Distler, and J. H. W. Distler, “Hypoxia. Hypoxia in the pathogenesis of systemic sclerosis,” Arthritis Research & Therapy, vol. 11, no. 2, p. 220, 2009. View at Scopus
  62. M. E. Anderson, T. L. Moore, S. Hollis, S. Clark, M. I. V. Jayson, and A. L. Herrick, “Endothelial-dependent vasodilatation is impaired in patients with systemic sclerosis, as assessed by low dose iontophoresis,” Clinical and Experimental Rheumatology, vol. 21, no. 3, article 403, 2003. View at Scopus
  63. R. Livi, L. Teghini, S. Generini, and M. Matucci-Cerinic, “The loss of endothelium-dependent vascular tone control in systemic sclerosis,” Chest, vol. 119, no. 2, pp. 672–673, 2001. View at Publisher · View at Google Scholar · View at Scopus
  64. B. Kahaleh and M. Matucci-Cerinic, “Raynaud's phenomenon and scleroderma: dysregulated neuroendothelial control of vascular tone,” Arthritis and Rheumatism, vol. 38, no. 1, pp. 1–4, 1995. View at Publisher · View at Google Scholar · View at Scopus
  65. J. Cailes, S. Winter, R. M. du Bois, and T. W. Evans, “Defective endothelially mediated pulmonary vasodilation in systemic sclerosis,” Chest, vol. 114, no. 1, pp. 178–184, 1998. View at Scopus
  66. A. Leask, “The role of endothelin-1 signaling in the fibrosis observed in systemic sclerosis,” Pharmacological Research, vol. 63, no. 6, pp. 502–503, 2011. View at Publisher · View at Google Scholar · View at Scopus
  67. N. Giordano, P. Papakostas, G. Pecetti, and R. Nuti, “Cytokine modulation by endothelin-1 and possible therapeutic implications in systemic sclerosis,” Journal of Biological Regulators and Homeostatic Agents, vol. 25, no. 4, pp. 487–492, 2011. View at Scopus
  68. K. Yamane, H. Kashiwagi, N. Suzuki et al., “Elevated plasma levels of endothelin-1 in systemic sclerosis,” Arthritis and Rheumatism, vol. 34, no. 2, pp. 243–244, 1991. View at Scopus
  69. K. Yamane, T. Miyauchi, N. Suzuki et al., “Significance of plasma endothelin-1 levels in patients with systemic sclerosis,” Journal of Rheumatology, vol. 19, no. 10, pp. 1566–1571, 1992. View at Scopus
  70. A. D. Cambrey, N. K. Harrison, K. E. Dawes et al., “Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro,” The American Journal of Respiratory Cell and Molecular Biology, vol. 11, no. 4, pp. 439–445, 1994. View at Scopus
  71. R. Vancheeswaran, T. Magoulas, G. Efrat et al., “Circulating endothelin-1 levels in systemic sclerosis subsets—a marker of fibrosis or vasular dysfunction?” Journal of Rheumatology, vol. 21, no. 10, pp. 1838–1844, 1994. View at Scopus
  72. S. Morelli, C. Ferri, E. Polettini et al., “Plasma endothelin-1 levels, pulmonary hypertension, and lung fibrosis in patients with systemic sclerosis,” The American Journal of Medicine, vol. 99, no. 3, pp. 255–260, 1995. View at Publisher · View at Google Scholar · View at Scopus
  73. S. Xu, C. P. Denton, A. Holmes, M. R. Dashwood, D. J. Abraham, and C. M. Black, “Endothelins: effect on matrix biosynthesis and proliferation in normal and scleroderma fibroblasts,” Journal of Cardiovascular Pharmacology, vol. 31, no. 1, pp. S360–S363, 1998. View at Scopus
  74. X. Shi-Wen, C. P. Denton, M. R. Dashwood et al., “Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1,” Journal of Investigative Dermatology, vol. 116, no. 3, pp. 417–425, 2001. View at Publisher · View at Google Scholar · View at Scopus
  75. X. Shi-Wen, E. A. Renzoni, L. Kennedy et al., “Endogenous endothelin-1 signaling contributes to type I collagen and CCN2 overexpression in fibrotic fibroblasts,” Matrix Biology, vol. 26, no. 8, pp. 625–632, 2007. View at Publisher · View at Google Scholar · View at Scopus
  76. X. Shi-wen, L. Kennedy, E. A. Renzoni et al., “Endothelin is a downstream mediator of profibrotic responses to transforming growth factor β in human lung fibroblasts,” Arthritis and Rheumatism, vol. 56, no. 12, pp. 4189–4194, 2007. View at Publisher · View at Google Scholar · View at Scopus
  77. I. Chrobak, S. Lenna, L. Stawski, and M. Trojanowska, “Interferon-γ promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) β2,” Journal of Cellular Physiology, vol. 228, no. 8, pp. 1774–1783, 2013. View at Publisher · View at Google Scholar
  78. A. E. Koch and O. Distler, “Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis,” Arthritis Research and Therapy, vol. 9, supplement 2, article S3, 2007. View at Publisher · View at Google Scholar · View at Scopus
  79. J. H. W. Distler, S. Gay, and O. Distler, “Angiogenesis and vasculogenesis in systemic sclerosis,” Rheumatology, vol. 45, no. 3, pp. iii26–iii27, 2006. View at Publisher · View at Google Scholar · View at Scopus
  80. J. Wipff, J. Avouac, D. Borderie et al., “Disturbed angiogenesis in systemic sclerosis: high levels of soluble endoglin,” Rheumatology, vol. 47, no. 7, pp. 972–975, 2008. View at Publisher · View at Google Scholar · View at Scopus
  81. N. Del Papa, N. Quirici, D. Soligo et al., “Bone marrow endothelial progenitors are defective in systemic sclerosis,” Arthritis and Rheumatism, vol. 54, no. 8, pp. 2605–2615, 2006. View at Publisher · View at Google Scholar · View at Scopus
  82. M. Kuwana, Y. Okazaki, H. Yasuoka, Y. Kawakami, and Y. Ikeda, “Defective vasculogenesis in systemic sclerosis,” The Lancet, vol. 364, no. 9434, pp. 603–610, 2004. View at Publisher · View at Google Scholar · View at Scopus
  83. O. Distler, J. H. W. Distler, A. Scheid et al., “Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis,” Circulation Research, vol. 95, no. 1, pp. 109–116, 2004. View at Publisher · View at Google Scholar · View at Scopus
  84. T. Nevskaya, S. Bykovskaia, E. Lyssuk et al., “Circulating endothelial progenitor cells in systemic sclerosis: relation to impaired angiogenesis and cardiovascular manifestations,” Clinical and Experimental Rheumatology, vol. 26, no. 3, pp. 421–429, 2008. View at Scopus
  85. P. Cipriani, S. Guiducci, I. Miniati et al., “Impairment of endothelial cell differentiation from bone marrow-derived mesenchymal stem cells: new insight into the pathogenesis of systemic sclerosis,” Arthritis and Rheumatism, vol. 56, no. 6, pp. 1994–2004, 2007. View at Publisher · View at Google Scholar · View at Scopus
  86. J. N. Fleming and S. M. Schwartz, “The pathology of scleroderma vascular disease,” Rheumatic Disease Clinics of North America, vol. 34, no. 1, pp. 41–55, 2008. View at Publisher · View at Google Scholar · View at Scopus
  87. F. J. de Lange, A. F. M. Moorman, R. H. Anderson et al., “Lineage and morphogenetic analysis of the cardiac valves,” Circulation Research, vol. 95, no. 6, pp. 645–654, 2004. View at Publisher · View at Google Scholar · View at Scopus
  88. E. Arciniegas, C. Y. Neves, L. M. Carrillo, E. A. Zambrano, and R. Ramírez, “Endothelial-mesenchymal transition occurs during embryonic pulmonary artery development,” Endothelium, vol. 12, no. 4, pp. 193–200, 2005. View at Publisher · View at Google Scholar · View at Scopus
  89. A. de Vlaming, K. Sauls, Z. Hajdu et al., “Atrioventricular valve development: new perspectives on an old theme,” Differentiation, vol. 84, no. 1, pp. 103–116, 2012. View at Publisher · View at Google Scholar
  90. S. Piera-Velazquez, Z. Li, and S. A. Jimenez, “Role of endothelial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders,” The American Journal of Pathology, vol. 179, no. 3, pp. 1074–1080, 2011. View at Publisher · View at Google Scholar · View at Scopus
  91. J. He, Y. Xu, and K. Kanasaki, “Role of endothelial-to-mesenchymal transition in renal fibrosis of chronic kidney disease,” Clinical and Experimental Nephrology, vol. 17, no. 4, pp. 488–497, 2013. View at Publisher · View at Google Scholar
  92. J. Li and J. F. Bertram, “Endothelial-myofibroblast transition, a new player in diabetic renal fibrosis,” Nephrology, vol. 15, no. 5, pp. 507–512, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. F. Rieder, S. P. Kessler, G. A. West et al., “Inflammation-induced endothelial-to-mesenchymal transition: a novel mechanism of intestinal fibrosis,” The American Journal of Pathology, vol. 179, no. 5, pp. 2660–2673, 2011. View at Publisher · View at Google Scholar · View at Scopus
  94. V. S. Lebleu, G. Taduri, J. O'Connell et al., “Origin and function of myofibroblasts in kidney fibrosis,” Nature Medicine, vol. 19, no. 8, pp. 1047–1053, 2013. View at Publisher · View at Google Scholar
  95. E. M. Zeisberg, S. E. Potenta, H. Sugimoto, M. Zeisberg, and R. Kalluri, “Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition,” Journal of the American Society of Nephrology, vol. 19, no. 12, pp. 2282–2287, 2008. View at Publisher · View at Google Scholar · View at Scopus
  96. E. M. Zeisberg, O. Tarnavski, M. Zeisberg et al., “Endothelial-to-mesenchymal transition contributes to cardiac fibrosis,” Nature Medicine, vol. 13, no. 8, pp. 952–961, 2007. View at Publisher · View at Google Scholar · View at Scopus
  97. A. Kizu, D. Medici, and R. Kalluri, “Endothelial-mesenchymal transition as a novel mechanism for generating myofibroblasts during diabetic nephropathy,” The American Journal of Pathology, vol. 175, no. 4, pp. 1371–1373, 2009. View at Publisher · View at Google Scholar · View at Scopus
  98. S. Speca, I. Giusti, F. Rieder, and G. Latella, “Cellular and molecular mechanisms of intestinal fibrosis,” World Journal of Gastroenterology, vol. 18, no. 28, pp. 3635–3661, 2012. View at Publisher · View at Google Scholar
  99. Y. Sato and Y. Nakanuma, “Role of endothelial-mesenchymal transition in idiopathic portal hypertension,” Histology and Histopathology, vol. 28, pp. 145–154, 2013.
  100. E. Arciniegas, M. G. Frid, I. S. Douglas, and K. R. Stenmark, “Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 293, no. 1, pp. L1–L8, 2007. View at Publisher · View at Google Scholar · View at Scopus
  101. S. Piera-Velazquez and S. A. Jimenez, “Molecular mechanisms of endothelial to mesenchymal cell transition (EndoMT) in experimentally induced fibrotic diseases,” Fibrogenesis and Tissue Repair, vol. 5, supplement 1, article S7, 2012.
  102. M. Goumans, Z. Liu, and P. T. Dijke, “TGF-β signaling in vascular biology and dysfunction,” Cell Research, vol. 19, no. 1, pp. 116–127, 2009. View at Publisher · View at Google Scholar · View at Scopus
  103. D. Medici, S. Potenta, and R. Kalluri, “Transforming growth factor-β2 promotes Snail-mediated endothelial—mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling,” Biochemical Journal, vol. 437, no. 3, pp. 515–520, 2011. View at Publisher · View at Google Scholar · View at Scopus
  104. L. A. van Meeteren and P. T. Dijke, “Regulation of endothelial cell plasticity by TGF-β,” Cell and Tissue Research, vol. 347, no. 1, pp. 177–186, 2012. View at Publisher · View at Google Scholar · View at Scopus
  105. M. B. Sporn, A. B. Roberts, L. M. Wakefield, and R. K. Assoian, “Transforming growth factor factor-β: biological function and chemical structure,” Science, vol. 233, no. 4763, pp. 532–534, 1986. View at Scopus
  106. A. B. Roberts, K. C. Flanders, U. I. Heine et al., “Transforming growth factor-beta: multifunctional regulator of differentiation and development,” Philosophical transactions of the Royal Society of London B, vol. 327, no. 1239, pp. 145–154, 1990. View at Scopus
  107. G. C. Blobe, W. P. Schiemann, and H. F. Lodish, “Role of transforming growth factor β in human disease,” The New England Journal of Medicine, vol. 342, no. 18, pp. 1350–1358, 2000. View at Publisher · View at Google Scholar · View at Scopus
  108. W. A. Border and N. A. Noble, “Transforming growth factor β in tissue fibrosis,” The New England Journal of Medicine, vol. 331, no. 19, pp. 1286–1292, 1994. View at Publisher · View at Google Scholar · View at Scopus
  109. R. A. Ignotz and J. Massagué, “Transforming growth factor-β stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix,” The Journal of Biological Chemistry, vol. 261, no. 9, pp. 4337–4345, 1986. View at Scopus
  110. J. Varga and S. A. Jimenez, “Stimulation of normal human fibroblast collagen production and processing by transforming growth factor,” Biochemical and Biophysical Research Communications, vol. 138, no. 2, pp. 974–980, 1986. View at Scopus
  111. J. Varga, J. Rosenbloom, and S. A. Jimenez, “Transforming growth factor β (TGFβ) causes a persistent increase in steady-state amounts of type I and type III collagen and fibronectin mRNAs in normal human dermal fibroblasts,” Biochemical Journal, vol. 247, no. 3, pp. 597–604, 1987. View at Scopus
  112. A. B. Roberts, U. I. Heine, K. C. Flanders, and M. B. Sporn, “Transforming growth factor-β. Major role in regulation of extracellular matrix,” Annals of the New York Academy of Sciences, vol. 580, pp. 225–232, 1990. View at Publisher · View at Google Scholar · View at Scopus
  113. R. J. McAnulty, J. S. Campa, A. D. Cambrey, and G. J. Laurent, “The effect of transforming growth factor β on rates of procollagen synthesis and degradation in vitro,” Biochimica et Biophysica Acta, vol. 1091, no. 2, pp. 231–235, 1991. View at Publisher · View at Google Scholar · View at Scopus
  114. D. R. Edwards, G. Murphy, J. J. Reynolds et al., “Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor,” EMBO Journal, vol. 6, no. 7, pp. 1899–1904, 1987. View at Scopus
  115. H. Ihn, “Autocrine TGF-β signaling in the pathogenesis of systemic sclerosis,” Journal of Dermatological Science, vol. 49, no. 2, pp. 103–113, 2008. View at Publisher · View at Google Scholar · View at Scopus
  116. Z. Li and S. A. Jimenez, “Protein kinase Cδ and c-Abl kinase are required for transforming growth factor β induction of endothelial-mesenchymal transition in vitro,” Arthritis and Rheumatism, vol. 63, no. 8, pp. 2473–2483, 2011. View at Publisher · View at Google Scholar · View at Scopus
  117. Y. Yoshimatsu and T. Watabe, “Roles of TGF-β signals in endothelial-mesenchymal transition during cardiac fibrosis,” International Journal of Inflammation, vol. 2011, Article ID 724080, 8 pages, 2011. View at Publisher · View at Google Scholar
  118. F. Lin, N. Wang, and T. C. Zhang, “The role of endothelial-mesenchymal transition in development and pathological process,” IUBMB Life, vol. 64, no. 9, pp. 717–723, 2012. View at Publisher · View at Google Scholar
  119. J. Garcia, M. J. Sandi, P. Cordelier et al., “Tie1 deficiency induces endothelial-mesenchymal transition,” EMBO Reports, vol. 13, no. 5, pp. 431–439, 2012. View at Publisher · View at Google Scholar · View at Scopus
  120. A. K. Ghosh, V. Nagpal, J. W. Covington, M. A. Michaels, and D. E. Vaughan, “Molecular basis of cardiac endothelial-to-mesenchymal transition (EndMT): differential expression of microRNAs during EndMT,” Cellular Signalling, vol. 24, no. 5, pp. 1031–1036, 2012. View at Publisher · View at Google Scholar · View at Scopus
  121. H. Mihira, H. I. Suzuki, Y. Akatsu et al., “TGF-β-induced mesenchymal transition of MS-1 endothelial cells requires Smad-dependent cooperative activation of Rho signals and MRTF-A,” Journal of Biochemistry, vol. 151, no. 2, pp. 145–156, 2012. View at Publisher · View at Google Scholar · View at Scopus
  122. M. Reis and S. Liebner, “Wnt signaling in the vasculature,” Experimental Cell Research, vol. 319, no. 9, pp. 1317–1323, 2013. View at Publisher · View at Google Scholar
  123. C. Niehrs, “The complex world of WNT receptor signalling,” Nature Reviews Molecular Cell Biology, vol. 13, pp. 767–779, 2012. View at Publisher · View at Google Scholar
  124. H. Clevers and R. Nusse, “Wnt/β-catenin signaling and disease,” Cell, vol. 149, no. 6, pp. 1192–1205, 2012. View at Publisher · View at Google Scholar
  125. P. Herr, G. Hausmann, and K. Basler, “WNT secretion and signalling in human disease,” Trends in Molecular Medicine, vol. 18, no. 8, pp. 483–493, 2012. View at Publisher · View at Google Scholar
  126. R. Lafyatis, “Connective tissue disease: SSc-fibrosis takes flight with Wingless inhibition,” Nature Reviews Rheumatology, vol. 8, pp. 441–442, 2012. View at Publisher · View at Google Scholar
  127. C. Beyer, A. Schramm, A. Akhmetshina et al., “β-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis,” Annals of the Rheumatic Diseases, vol. 71, no. 5, pp. 761–767, 2012. View at Publisher · View at Google Scholar · View at Scopus
  128. J. Wei, F. Fang, A. P. Lam et al., “Wnt/β-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells,” Arthritis and Rheumatism, vol. 64, no. 8, pp. 2734–2745, 2012. View at Publisher · View at Google Scholar
  129. A. P. Lam, A. S. Flozak, S. Russell et al., “Nuclear β-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation,” The American Journal of Respiratory Cell and Molecular Biology, vol. 45, no. 5, pp. 915–922, 2011. View at Publisher · View at Google Scholar · View at Scopus
  130. L. Attisano and E. Labbé, “TGFβ and Wnt pathway cross-talk,” Cancer and Metastasis Reviews, vol. 23, no. 1-2, pp. 53–61, 2004. View at Publisher · View at Google Scholar · View at Scopus
  131. P. Minoo and C. Li, “Cross-talk between transforming growth factor-β and Wingless/Int pathways in lung development and disease,” International Journal of Biochemistry and Cell Biology, vol. 42, no. 6, pp. 809–812, 2010. View at Publisher · View at Google Scholar · View at Scopus
  132. P. Zhang, Y. Cai, A. Soofi, and G. R. Dressler, “Activation of Wnt11 by transforming growth factor-β drives mesenchymal gene expression through non-canonical Wnt protein signaling in renal epithelial cells,” The Journal of Biological Chemistry, vol. 287, no. 25, pp. 21290–21302, 2012. View at Publisher · View at Google Scholar
  133. A. Akhmetshina, K. Palumbo, C. Dees et al., “Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis,” Nature Communications, vol. 3, article 734, 2012. View at Publisher · View at Google Scholar · View at Scopus
  134. R. Kalluri and E. G. Neilson, “Epithelial-mesenchymal transition and its implications for fibrosis,” Journal of Clinical Investigation, vol. 112, no. 12, pp. 1776–1784, 2003. View at Publisher · View at Google Scholar · View at Scopus
  135. M. A. Nieto, “The ins and outs of the epithelial to mesenchymal transition in health and disease,” Annual Review of Cell and Developmental Biology, vol. 27, pp. 347–376, 2011. View at Publisher · View at Google Scholar · View at Scopus
  136. J. P. Thiery, H. Acloque, R. Y. J. Huang, and M. A. Nieto, “Epithelial-mesenchymal transitions in development and disease,” Cell, vol. 139, no. 5, pp. 871–890, 2009. View at Publisher · View at Google Scholar · View at Scopus
  137. K. Lee and C. M. Nelson, “New insights into the regulation of epithelial-mesenchymal transition and tissue fibrosis,” International Review of Cell and Molecular Biology, vol. 294, pp. 171–221, 2012. View at Publisher · View at Google Scholar · View at Scopus
  138. S. L. Cheng, J. S. Shao, A. Behrmann, K. Krchma, and D. A. Towler, “Dkk1 and MSX2-wnt7b signaling reciprocally regulate the endothelial-mesenchymal transition in aortic endothelial cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, pp. 1679–1689, 2013. View at Publisher · View at Google Scholar
  139. S. J. Bray, “Notch signalling: a simple pathway becomes complex,” Nature Reviews Molecular Cell Biology, vol. 7, no. 9, pp. 678–689, 2006. View at Publisher · View at Google Scholar · View at Scopus
  140. R. Kopan and M. X. G. Ilagan, “The canonical notch signaling pathway: unfolding the activation mechanism,” Cell, vol. 137, no. 2, pp. 216–233, 2009. View at Publisher · View at Google Scholar · View at Scopus
  141. A. Louvi and S. Artavanis-Tsakonas, “Notch and disease: a growing field,” Seminars in Cell and Developmental Biology, vol. 23, no. 4, pp. 473–480, 2012. View at Publisher · View at Google Scholar · View at Scopus
  142. A. L. Penton, L. D. Leonard, and N. B. Spinner, “Notch signaling in human development and disease,” Seminars in Cell and Developmental Biology, vol. 23, no. 4, pp. 450–457, 2012. View at Publisher · View at Google Scholar · View at Scopus
  143. R. A. Benson, J. A. Lowrey, J. R. Lamb, and S. E. M. Howie, “The Notch and Sonic hedgehog signalling pathways in immunity,” Molecular Immunology, vol. 41, no. 6-7, pp. 715–725, 2004. View at Publisher · View at Google Scholar · View at Scopus
  144. F. Radtke, A. Wilson, S. J. C. Mancini, and H. R. MacDonald, “Notch regulation of lymphocyte development and function,” Nature Immunology, vol. 5, no. 3, pp. 247–253, 2004. View at Publisher · View at Google Scholar · View at Scopus
  145. L. E. Laitman and S. Dahan, “Taking inflammatory bowel disease up a Notch,” Immunologic Research, vol. 54, no. 1–3, pp. 69–74, 2012. View at Publisher · View at Google Scholar
  146. R. Bonegio and K. Susztak, “Notch signaling in diabetic nephropathy,” Experimental Cell Research, vol. 318, no. 9, pp. 986–992, 2012. View at Publisher · View at Google Scholar · View at Scopus
  147. N. Sethi and Y. Kang, “Notch signalling in cancer progression and bone metastasis,” The British Journal of Cancer, vol. 105, no. 12, pp. 1805–1810, 2011. View at Publisher · View at Google Scholar · View at Scopus
  148. M. Noseda, G. McLean, K. Niessen et al., “Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation,” Circulation Research, vol. 94, no. 7, pp. 910–917, 2004. View at Publisher · View at Google Scholar · View at Scopus
  149. M. Noseda, Y. Fu, K. Niessen et al., “Smooth muscle α-actin is a direct target of Notch/CSL,” Circulation Research, vol. 98, no. 12, pp. 1468–1470, 2006. View at Publisher · View at Google Scholar · View at Scopus
  150. K. Niessen, Y. Fu, L. Chang, P. A. Hoodless, D. McFadden, and A. Karsan, “Slug is a direct Notch target required for initiation of cardiac cushion cellularization,” Journal of Cell Biology, vol. 182, no. 2, pp. 315–325, 2008. View at Publisher · View at Google Scholar · View at Scopus
  151. Y. X. Fu, A. Chang, L. Chang et al., “Differential regulation of transforming growth factor β signaling pathways by Notch in human endothelial cells,” The Journal of Biological Chemistry, vol. 284, no. 29, pp. 19452–19462, 2009. View at Publisher · View at Google Scholar · View at Scopus
  152. Y. Fu, A. C. Y. Chang, M. Fournier, L. Chang, K. Niessen, and A. Karsan, “RUNX3 maintains the mesenchymal phenotype after termination of the notch signal,” The Journal of Biological Chemistry, vol. 286, no. 13, pp. 11803–11813, 2011. View at Publisher · View at Google Scholar · View at Scopus
  153. A. C. Y. Chang, Y. Fu, V. C. Garside et al., “Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase,” Developmental Cell, vol. 21, no. 2, pp. 288–300, 2011. View at Publisher · View at Google Scholar · View at Scopus
  154. V. C. Garside, A. C. Chang, A. Karsan, and P. A. Hoodless, “Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development,” Cellular and Molecular Life Sciences, vol. 70, no. 16, pp. 2899–2917, 2013. View at Publisher · View at Google Scholar
  155. C. Beyer and J. H. Distler, “Morphogen pathways in systemic sclerosis,” Current Rheumatology Reports, vol. 15, no. 1, article 299, 2013. View at Publisher · View at Google Scholar
  156. C. Beyer, C. Dees, and J. H. Distler, “Morphogen pathways as molecular targets for the treatment of fibrosis in systemic sclerosis,” Archives of Dermatological Research, vol. 305, no. 1, pp. 1–8, 2013. View at Publisher · View at Google Scholar
  157. G. M. Di Guglielmo, C. Le Roy, A. F. Goodfellow, and J. L. Wrana, “Distinct endocytic pathways regulate TGF-β receptor signalling and turnover,” Nature Cell Biology, vol. 5, no. 5, pp. 410–421, 2003. View at Publisher · View at Google Scholar · View at Scopus
  158. S. Hayes, A. Chawla, and S. Corvera, “TGFβ receptor internalization into EEA1-enriched early endosomes: role in signaling to Smad2,” Journal of Cell Biology, vol. 158, no. 7, pp. 1239–1249, 2002. View at Publisher · View at Google Scholar · View at Scopus
  159. C. E. Runyan, H. W. Schnaper, and A. Poncelet, “The role of internalization in transforming growth factor β1-induced Smad2 association with Smad anchor for receptor activation (SARA) and Smad2-dependent signaling in human mesangial cells,” The Journal of Biological Chemistry, vol. 280, no. 9, pp. 8300–8308, 2005. View at Publisher · View at Google Scholar · View at Scopus
  160. F. Del Galdo, M. R. Lisanti, and S. A. Jimenez, “Caveolin-1, transforming growth factor-β receptor internalization, and the pathogenesis of systemic sclerosis,” Current Opinion in Rheumatology, vol. 20, no. 6, pp. 713–719, 2008. View at Publisher · View at Google Scholar · View at Scopus
  161. F. Del Galdo, F. Sotgia, C. J. De Almeida et al., “Decreased expression of caveolin 1 in patients with systemic sclerosis: crucial role in the pathogenesis of tissue fibrosis,” Arthritis and Rheumatism, vol. 58, no. 9, pp. 2854–2865, 2008. View at Publisher · View at Google Scholar · View at Scopus
  162. E. Tourkina, M. Richard, P. Gööz et al., “Antifibrotic properties of caveolin-1 scaffolding domain in vitro and in vivo,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 294, no. 5, pp. L843–L861, 2008. View at Publisher · View at Google Scholar · View at Scopus
  163. O. Le Saux, K. Teeters, S. Miyasato et al., “The role of caveolin-1 in pulmonary matrix remodeling and mechanical properties,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 295, no. 6, pp. L1007–L1017, 2008. View at Publisher · View at Google Scholar · View at Scopus
  164. E. Tourkina, M. Bonner, J. Oates et al., “Altered monocyte and fibrocyte phenotype and function in scleroderma interstitial lung disease: reversal by caveolin-1 scaffolding domain peptide,” Fibrogenesis and Tissue Repair, vol. 4, no. 1, article 15, 2011. View at Publisher · View at Google Scholar · View at Scopus
  165. Z. Li, P. J. Wermuth, B. S. Benn, M. P. Lisanti, and S. A. Jimenez, “Caveolin-1 deficiency induces spontaneous endothelial-to-mesenchymal transition in murine pulmonary endothelial cells in vitro,” The American Journal of Pathology, vol. 182, no. 2, pp. 325–331, 2013. View at Publisher · View at Google Scholar
  166. S. A. Jiménez, S. V. Castro, and S. Piera-Velázquez, “Role of growth factors in the pathogenesis of tissue fibrosis in systemic sclerosis,” Current Rheumatology Reviews, vol. 6, no. 4, pp. 283–294, 2010. View at Publisher · View at Google Scholar · View at Scopus
  167. M. Trojanowska, “Role of PDGF in fibrotic diseases and systemic sclerosis,” Rheumatology, vol. 47, supplement, pp. v2–v4, 2008. View at Scopus
  168. M. Bielecki, K. Kowal, A. Lapinska, S. Chwiesko-Minarowska, L. Chyczewski, and O. Kowal-Bielecka, “Peripheral blood mononuclear cells from patients with systemic sclerosis spontaneously secrete increased amounts of vascular endothelial growth factor (VEGF) already in the early stage of the disease,” Advances in Medical Sciences, vol. 56, no. 2, pp. 255–263, 2011. View at Publisher · View at Google Scholar · View at Scopus
  169. P. M. Krein and B. W. Winston, “Roles for insulin-like growth factor I and transforming growth factor-β in fibrotic lung disease,” Chest, vol. 122, no. 6, supplement, pp. 289S–293S, 2002. View at Scopus
  170. B. Widyantoro, N. Emoto, K. Nakayama et al., “Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition,” Circulation, vol. 121, no. 22, pp. 2407–2418, 2010. View at Publisher · View at Google Scholar · View at Scopus
  171. G. R. Grotendorst, “Connective tissue growth factor: a mediator of TGf-β action on fibroblasts,” Cytokine and Growth Factor Reviews, vol. 8, no. 3, pp. 171–179, 1997. View at Publisher · View at Google Scholar · View at Scopus
  172. A. Leask and D. J. Abraham, “The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology,” Biochemistry and Cell Biology, vol. 81, no. 6, pp. 355–363, 2003. View at Publisher · View at Google Scholar · View at Scopus
  173. A. Leask and D. J. Abraham, “All in the CCN family: essential matricellular signaling modulators emerge from the bunker,” Journal of Cell Science, vol. 119, no. 23, pp. 4803–4810, 2006. View at Publisher · View at Google Scholar · View at Scopus
  174. X. Shi-Wen, A. Leask, and D. Abraham, “Regulation and function of connective tissue growth factor/CCN2 in tissue repair, scarring and fibrosis,” Cytokine and Growth Factor Reviews, vol. 19, no. 2, pp. 133–144, 2008. View at Publisher · View at Google Scholar · View at Scopus
  175. A. Leask, C. P. Denton, and D. J. Abraham, “Insights into the molecular mechanism of chronic fibrosis: the role of connective tissue growth factor in scleroderma,” Journal of Investigative Dermatology, vol. 122, no. 1, pp. 1–6, 2004. View at Publisher · View at Google Scholar · View at Scopus
  176. C. P. Denton and D. J. Abraham, “Transforming growth factor-β and connective tissue growth factor: key cytokines in scleroderma pathogenesis,” Current Opinion in Rheumatology, vol. 13, no. 6, pp. 505–511, 2001. View at Publisher · View at Google Scholar · View at Scopus
  177. A. Igarashi, K. Nashiro, K. Kikuchi et al., “Significant correlation between connective tissue growth factor gene expression and skin sclerosis in tissue sections from patients with systemic sclerosis,” Journal of Investigative Dermatology, vol. 105, no. 2, pp. 280–284, 1995. View at Scopus
  178. S. Serratì, A. Chillà, A. Laurenzana et al., “Systemic sclerosis endothelial cells recruit and activate dermal fibroblasts by induction of a connective tissue growth factor (CCN2)/transforming growth factor β-dependent mesenchymal-to-mesenchymal transition,” Arthritis and Rheumatism, vol. 65, no. 1, pp. 258–269, 2013. View at Publisher · View at Google Scholar
  179. S. W. Lee, J. Y. Won, W. J. Kim et al., “Snail as a potential target molecule in cardiac fibrosis: paracrine action of endothelial cells on fibroblasts through Snail and CTGF axis,” Molecular Therapy, 2013. View at Publisher · View at Google Scholar
  180. D. P. Bartel, “MicroRNAs: genomics, biogenesis, mechanism, and function,” Cell, vol. 116, no. 2, pp. 281–297, 2004. View at Publisher · View at Google Scholar · View at Scopus
  181. X. Liu, K. Fortin, and Z. Mourelatos, “MicroRNAs: biogenesis and molecular functions,” Brain Pathology, vol. 18, no. 1, pp. 113–121, 2008. View at Publisher · View at Google Scholar · View at Scopus
  182. T. Treiber, N. Treiber, and G. Meister, “Regulation of microRNA biogenesis and function,” Thrombosis and Haemostasis, vol. 107, no. 4, pp. 605–610, 2012. View at Publisher · View at Google Scholar · View at Scopus
  183. I. G. Cannell, Y. W. Kong, and M. Bushell, “How do microRNAs regulate gene expression?” Biochemical Society Transactions, vol. 36, no. 6, pp. 1224–1231, 2008. View at Publisher · View at Google Scholar · View at Scopus
  184. A. Eulalio, E. Huntzinger, and E. Izaurralde, “Getting to the root of miRNA-mediated gene silencing,” Cell, vol. 132, no. 1, pp. 9–14, 2008. View at Publisher · View at Google Scholar · View at Scopus
  185. M. R. Fabian, N. Sonenberg, and W. Filipowicz, “Regulation of mRNA translation and stability by microRNAs,” Annual Review of Biochemistry, vol. 79, pp. 351–379, 2010. View at Publisher · View at Google Scholar · View at Scopus
  186. M. V. Iorio and C. M. Croce, “MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review,” EMBO Molecular Medicine, vol. 4, no. 3, pp. 143–159, 2012. View at Publisher · View at Google Scholar · View at Scopus
  187. X. Jiang, E. Tsitsiou, S. E. Herrick, and M. A. Lindsay, “MicroRNAs and the regulation of fibrosis,” FEBS Journal, vol. 277, no. 9, pp. 2015–2021, 2010. View at Publisher · View at Google Scholar · View at Scopus
  188. S. Vettori, S. Gay, and O. Distler, “Role of MicroRNAs in fibrosis,” Open Rheumatology Journal, vol. 6, pp. 130–139, 2012. View at Publisher · View at Google Scholar
  189. V. Patel and L. Noureddine, “MicroRNAs and fibrosis,” Current Opinion in Nephrology and Hypertension, vol. 21, no. 4, pp. 410–416, 2012. View at Publisher · View at Google Scholar
  190. T. Bowen, R. H. Jenkins, and D. J. Fraser, “MicroRNAs, transforming growth factor β-1, and tissue fibrosis,” Journal of Pathology, vol. 229, no. 2, pp. 274–285, 2013. View at Publisher · View at Google Scholar
  191. B. Maurer, J. Stanczyk, A. Jüngel et al., “MicroRNA-29, a key regulator of collagen expression in systemic sclerosis,” Arthritis and Rheumatism, vol. 62, no. 6, pp. 1733–1743, 2010. View at Publisher · View at Google Scholar · View at Scopus
  192. H. Zhu, Y. Li, S. Qu et al., “MicroRNA expression abnormalities in limited cutaneous scleroderma and diffuse cutaneous scleroderma,” Journal of Clinical Immunology, vol. 32, no. 3, pp. 514–522, 2012. View at Publisher · View at Google Scholar · View at Scopus
  193. N. Honda, M. Jinnin, I. Kajihara et al., “TGF-β-mediated downregulation of microRNA-196a contributes to the constitutive upregulated type I collagen expression in scleroderma dermal fibroblasts,” Journal of Immunology, vol. 188, no. 7, pp. 3323–3331, 2012. View at Publisher · View at Google Scholar · View at Scopus
  194. T. Sing, M. Jinnin, K. Yamane et al., “microRNA-92a expression in the sera and dermal fibroblasts increases in patients with scleroderma,” Rheumatology, vol. 51, no. 9, pp. 1550–1556, 2012. View at Publisher · View at Google Scholar
  195. W. J. Peng, J. H. Tao, B. Mei et al., “MicroRNA-29: a potential therapeutic target for systemic sclerosis,” Expert Opinion on Therapeutic Targets, vol. 16, no. 9, pp. 875–879, 2012. View at Publisher · View at Google Scholar
  196. N. Honda, M. Jinnin, T. Kira-Etoh et al., “miR-150 down-regulation contributes to the constitutive type I collagen overexpression in scleroderma dermal fibroblasts via the induction of integrin β3,” The American Journal of Pathology, vol. 182, no. 1, pp. 206–216, 2013. View at Publisher · View at Google Scholar
  197. K. Makino, M. Jinnin, J. Aoi et al., “Discoidin domain receptor 2-microRNA 196a-mediated negative feedback against excess type I collagen expression is impaired in scleroderma dermal fibroblasts,” Journal of Investigative Dermatology, vol. 133, pp. 110–119, 2013. View at Publisher · View at Google Scholar
  198. J. Martin, R. H. Jenkins, R. Bennagi et al., “Post-transcriptional regulation of transforming growth factor β-1 by microRNA-744,” PLoS ONE, vol. 6, no. 10, Article ID e25044, 2011. View at Publisher · View at Google Scholar · View at Scopus
  199. J. P. Hong, X. M. Li, M. X. Li, and F. L. Zheng, “VEGF suppresses epithelial-mesenchymal transition by inhibiting the expression of Smad3 and miR-192, a Smad3-dependent microRNA,” International Journal of Molecular Medicine, vol. 31, no. 6, pp. 1436–1442, 2013. View at Publisher · View at Google Scholar
  200. R. Kumarswamy, I. Volkmann, V. Jazbutyte, S. Dangwal, D. Park, and T. Thum, “Transforming growth factor-β-induced endothelial-to-mesenchymal transition is partly mediated by MicroRNA-21,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 2, pp. 361–369, 2012. View at Publisher · View at Google Scholar · View at Scopus
  201. B. Hu and S. H. Phan, “Myofibroblasts,” Current Opinion in Rheumatology, vol. 25, no. 1, pp. 71–77, 2013. View at Publisher · View at Google Scholar
  202. B. Hinz, S. H. Phan, V. J. Thannickal et al., “Recent developments in myofibroblast biology: paradigms for connective tissue remodeling,” The American Journal of Pathology, vol. 180, no. 4, pp. 1340–1355, 2012. View at Publisher · View at Google Scholar · View at Scopus
  203. M. A. Watsky, K. T. Weber, Y. Sun, and A. Postlethwaite, “New insights into the mechanism of fibroblast to myofibroblast transformation and associated pathologies,” International Review of Cell and Molecular Biology, vol. 282, pp. 165–192, 2010. View at Publisher · View at Google Scholar · View at Scopus
  204. A. J. Gilbane, C. P. Denton, and A. M. Holmes, “Scleroderma pathogenesis: a pivotal role for fibroblasts as effector cells,” Arthritis Research and Therapy, vol. 15, no. 3, article 215, 2013.
  205. J. Wei, S. Bhattacharyya, W. G. Tourtellotte, and J. Varga, “Fibrosis in systemic sclerosis: emerging concepts and implications for targeted therapy,” Autoimmunity Reviews, vol. 10, no. 5, pp. 267–275, 2011. View at Publisher · View at Google Scholar · View at Scopus
  206. A. Leask, “Towards an anti-fibrotic therapy for scleroderma: targeting myofibroblast differentiation and recruitment,” Fibrogenesis and Tissue Repair, vol. 3, no. 1, article 8, 2010. View at Publisher · View at Google Scholar · View at Scopus
  207. A. E. Postlethwaite, H. Shigemitsu, and S. Kanangat, “Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis,” Current Opinion in Rheumatology, vol. 16, no. 6, pp. 733–738, 2004. View at Publisher · View at Google Scholar · View at Scopus
  208. M. Manetti, S. Guiducci, and M. Matucci-Cerinic, “The origin of the myofibroblast in fibroproliferative vasculopathy: does the endothelial cell steer the pathophysiology of systemic sclerosis?” Arthritis and Rheumatism, vol. 63, no. 8, pp. 2164–2167, 2011. View at Publisher · View at Google Scholar · View at Scopus