Current Rheumatology Reports

, Volume 14, Issue 1, pp 56–63 | Cite as

Angiogenesis and Vasculopathy in Systemic Sclerosis: Evolving Concepts

SCLERODERMA (J VARGA, SECTION EDITOR)

Abstract

Systemic sclerosis (scleroderma [SSc]) is a multifactorial disease characterized by inflammation, extensive and progressive fibrosis, and multiple vasculopathies. The vascular manifestations can be seen early in the pathogenesis of the disease and include malformed capillaries, Raynaud’s phenomenon, and digital ulcers. As the disease progresses, the vasculopathy proceeds to significant clinical manifestations, including renal crisis and pulmonary arterial hypertension. Moreover, later stages of the disease are marked by increasingly avascular areas. Despite the obliteration of microvascular structures, compensatory vasculogenesis and angiogenesis do not occur normally. This is in spite of a general increase in many potent angiogenic factors. Recent studies are beginning to examine this paradox and subsequent paucity of an angiogenic response in SSc. In this review, we discuss these findings and examine the role that chemokine and growth factor receptors, proteases, adhesion molecules, and transcription factors play in the dysregulation of angiogenesis in SSc.

Keywords

Systemic sclerosis Scleroderma Angiogenesis Vasculopathy Vasculogenesis Endothelial cells 

Notes

Acknowledgments

This work was supported by the National Institutes of Health (grant no. HL094017 to Dr. Rabquer), the Office of Research and Development, Medical Research Service, Department of Veterans Affairs, the Frederick G.L. Huetwell and William D. Robinson, MD, Professorship in Rheumatology, and by the Scleroderma Foundation (Mark Flapan Award).

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    • Gabrielli A, Avvedimento EV, Krieg T: Scleroderma. N Engl J Med 2009, 360(19):1989–2003. This is an excellent recent review on the pathogenesis of SSc. PubMedCrossRefGoogle Scholar
  2. 2.
    Maricq HR. Wide-field capillary microscopy. Arthritis Rheum. 1981;24(9):1159–65.PubMedCrossRefGoogle Scholar
  3. 3.
    Lambova SN, Muller-Ladner U. Capillaroscopic pattern in systemic sclerosis—an association with dynamics of processes of angio- and vasculogenesis. Microvasc Res. 2010;80(3):534–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Hachulla E, Clerson P, Launay D, et al. Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study. J Rheumatol. 2007;34(12):2423–30.PubMedGoogle Scholar
  5. 5.
    Lambova S, Muller-Ladner U. Pulmonary arterial hypertension in systemic sclerosis. Autoimmun Rev. 2010;9(11):761–70.PubMedCrossRefGoogle Scholar
  6. 6.
    Campo A, Mathai SC, Le Pavec J, et al. Hemodynamic predictors of survival in scleroderma-related pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;182(2):252–60.PubMedCrossRefGoogle Scholar
  7. 7.
    Denton CP, Lapadula G, Mouthon L, Muller-Ladner U. Renal complications and scleroderma renal crisis. Rheumatology (Oxford). 2009;48 Suppl 3:iii32–5.CrossRefGoogle Scholar
  8. 8.
    Au K, Singh MK, Bodukam V et al.: Atherosclerosis in systemic sclerosis—a systematic review and meta analysis. Arthritis Rheum 2011, Epub ahead of print.Google Scholar
  9. 9.
    Peichev M, Naiyer AJ, Pereira D, et al. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood. 2000;95(3):952–8.PubMedGoogle Scholar
  10. 10.
    Manetti M, Guiducci S, Ibba-Manneschi L, Matucci-Cerinic M. Mechanisms in the loss of capillaries in systemic sclerosis: angiogenesis versus vasculogenesis. J Cell Mol Med. 2010;14(6A):1241–54.PubMedCrossRefGoogle Scholar
  11. 11.
    Kuwana M, Okazaki Y, Yasuoka H, et al. Defective vasculogenesis in systemic sclerosis. Lancet. 2004;364(9434):603–10.PubMedCrossRefGoogle Scholar
  12. 12.
    Allanore Y, Batteux F, Avouac J, et al. Levels of circulating endothelial progenitor cells in systemic sclerosis. Clin Exp Rheumatol. 2007;25(1):60–6.PubMedGoogle Scholar
  13. 13.
    Avouac J, Juin F, Wipff J, et al. Circulating endothelial progenitor cells in systemic sclerosis: association with disease severity. Ann Rheum Dis. 2008;67(10):1455–60.PubMedCrossRefGoogle Scholar
  14. 14.
    Del Papa N, Quirici N, Soligo D, et al. Bone marrow endothelial progenitors are defective in systemic sclerosis. Arthritis Rheum. 2006;54(8):2605–15.PubMedCrossRefGoogle Scholar
  15. 15.
    Distler JH, Allanore Y, Avouac J, et al. EULAR Scleroderma Trials and Research group statement and recommendations on endothelial precursor cells. Ann Rheum Dis. 2009;68(2):163–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004;95(4):343–53.PubMedCrossRefGoogle Scholar
  17. 17.
    Jujo K, Ii M, Losordo DW. Endothelial progenitor cells in neovascularization of infarcted myocardium. J Mol Cell Cardiol. 2008;45(4):530–44.PubMedCrossRefGoogle Scholar
  18. 18.
    •• Yamaguchi Y, Okazaki Y, Seta N et al.: Enhanced angiogenic potency of monocytic endothelial progenitor cells in patients with systemic sclerosis. Arthritis Res Ther 2010, 12(6):R205. This was the first study to describe monocytic EPCs in SSc. The report further demonstrates that vasculogenesis is impaired in SSc and shows how monocytic EPCs may play a role in angiogenesis. PubMedCrossRefGoogle Scholar
  19. 19.
    Kaminski MJ, Majewski S, Jablonska S, Pawinska M. Lowered angiogeneic capability of peripheral blood lymphocytes in progressive systemic sclerosis (scleroderma). J Invest Dermatol. 1984;82(3):239–43.PubMedCrossRefGoogle Scholar
  20. 20.
    Majewski S, Skopinska-Rozewska E, Jablonska S, et al. Modulatory effect of sera from scleroderma patients on lymphocyte-induced angiogenesis. Arthritis Rheum. 1985;28(10):1133–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Koch AE, Polverini PJ, Leibovich SJ. Induction of neovascularization by activated human monocytes. J Leukoc Biol. 1986;39:233–8.PubMedGoogle Scholar
  22. 22.
    Marczak M, Majewski S, Skopinska-Rozewska E, et al. Enhanced angiogenic capability of monocyte-enriched mononuclear cell suspensions from patients with systemic scleroderma. J Invest Dermatol. 1986;86(4):355–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Kahaleh MB, DeLustro F, Bock W, LeRoy EC. Human monocyte modulation of endothelial cells and fibroblast growth: possible mechanism for fibrosis. Clin Immunol Immunopathol. 1986;39(2):242–55.PubMedCrossRefGoogle Scholar
  24. 24.
    Liakouli V, Cipriani P, Marrelli A et al.: Angiogenic cytokines and growth factors in systemic sclerosis. Autoimmun Rev 2011.Google Scholar
  25. 25.
    •• Margheri F, Serrati S, Lapucci A et al.: Modulation of the angiogenic phenotype of normal and systemic sclerosis endothelial cells by gain-loss of function of pentraxin 3 and matrix metalloproteinase 12. Arthritis Rheum 2010, 62(8):2488–2498. This excellent study expanded on the observation that MMP-12 and pentraxin 3 are overexpressed in SSc by performing an in vitro analysis of their role in angiogenesis. The authors showed that overexpressing both molecules in healthy ECs resulted in an inhibition of angiogenesis. They also found that SSc ECs do not mount an angiogenic response to bFGF or VEGF. PubMedCrossRefGoogle Scholar
  26. 26.
    Mackiewicz Z, Sukura A, Povilenaite D, et al. Increased but imbalanced expression of VEGF and its receptors has no positive effect on angiogenesis in systemic sclerosis skin. Clin Exp Rheumatol. 2002;20(5):641–6.PubMedGoogle Scholar
  27. 27.
    Distler O, Distler JH, Scheid A, et al. Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circ Res. 2004;95(1):109–16.PubMedCrossRefGoogle Scholar
  28. 28.
    Davies CA, Jeziorska M, Freemont AJ, Herrick AL. The differential expression of VEGF, VEGFR-2, and GLUT-1 proteins in disease subtypes of systemic sclerosis. Hum Pathol. 2006;37(2):190–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Carulli MT, Ong VH, Ponticos M, et al. Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts: evidence for autocrine regulation of myofibroblast differentiation. Arthritis Rheum. 2005;52(12):3772–82.PubMedCrossRefGoogle Scholar
  30. 30.
    • Rabquer BJ, Tsou P, Hou Y et al.: Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosis. Arthritis Res Ther 2011, 13(1):R18. This study provides further evidence of the importance of determining the expression of both angiogenic mediators and their receptors. It demonstrated that while antiangiogenic chemokines are elevated in SSc, their receptor is downregulated, thus limiting their impact. PubMedCrossRefGoogle Scholar
  31. 31.
    Cipriani P, Franca Milia A, Liakouli V, et al. Differential expression of stromal cell-derived factor 1 and its receptor CXCR4 in the skin and endothelial cells of systemic sclerosis patients: pathogenetic implications. Arthritis Rheum. 2006;54(9):3022–33.PubMedCrossRefGoogle Scholar
  32. 32.
    Rabquer BJ, Boychev G, Ruth JH, et al. Soluble junctional adhesion molecule-A promotes angiogenesis in rheumatoid arthritis. Arthritis Rheum. 2010;62:S590.CrossRefGoogle Scholar
  33. 33.
    Hou Y, Rabquer BJ, Gerber ML, et al. Junctional adhesion molecule-A is abnormally expressed in diffuse cutaneous systemic sclerosis skin and mediates myeloid cell adhesion. Ann Rheum Dis. 2009;69(1):249–54.CrossRefGoogle Scholar
  34. 34.
    Naik MU, Mousa SA, Parkos CA, Naik UP. Signaling through JAM-1 and alphavbeta3 is required for the angiogenic action of bFGF: dissociation of the JAM-1 and alphavbeta3 complex. Blood. 2003;102(6):2108–14.PubMedCrossRefGoogle Scholar
  35. 35.
    D’Alessio S, Fibbi G, Cinelli M, et al. Matrix metalloproteinase 12-dependent cleavage of urokinase receptor in systemic sclerosis microvascular endothelial cells results in impaired angiogenesis. Arthritis Rheum. 2004;50(10):3275–85.PubMedCrossRefGoogle Scholar
  36. 36.
    Giusti B, Fibbi G, Margheri F, et al. A model of anti-angiogenesis: differential transcriptosome profiling of microvascular endothelial cells from diffuse systemic sclerosis patients. Arthritis Res Ther. 2006;8(4):R115.PubMedCrossRefGoogle Scholar
  37. 37.
    Serrati S, Cinelli M, Margheri F, et al. Systemic sclerosis fibroblasts inhibit in vitro angiogenesis by MMP-12-dependent cleavage of the endothelial cell urokinase receptor. J Pathol. 2006;210(2):240–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Manetti M, Allanore Y, Revillod L, et al. A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis. Arthritis Rheum. 2011;63(1):247–56.PubMedCrossRefGoogle Scholar
  39. 39.
    Dean RA, Cox JH, Bellac CL, et al. Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR + CXC chemokines and generates CCL2, −7, −8, and −13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx. Blood. 2008;112(8):3455–64.PubMedCrossRefGoogle Scholar
  40. 40.
    Giusti B, Serrati S, Margheri F, et al. The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis. Arthritis Rheum. 2005;52(11):3618–28.PubMedCrossRefGoogle Scholar
  41. 41.
    Margheri F, Manetti M, Serrati S, et al. Domain 1 of the urokinase-type plasminogen activator receptor is required for its morphologic and functional, beta2 integrin-mediated connection with actin cytoskeleton in human microvascular endothelial cells: failure of association in systemic sclerosis endothelial cells. Arthritis Rheum. 2006;54(12):3926–38.PubMedCrossRefGoogle Scholar
  42. 42.
    Wagner EF. Bone development and inflammatory disease is regulated by AP-1 (Fos/Jun). Ann Rheum Dis. 2010;69 Suppl 1:i86–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Eferl R, Zenz R, Theussl HC, Wagner EF. Simultaneous generation of fra-2 conditional and fra-2 knock-out mice. Genesis. 2007;45(7):447–51.PubMedCrossRefGoogle Scholar
  44. 44.
    Eferl R, Hasselblatt P, Rath M, et al. Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1. Proc Natl Acad Sci USA. 2008;105(30):10525–30.PubMedCrossRefGoogle Scholar
  45. 45.
    •• Maurer B, Busch N, Jungel A et al.: Transcription factor fos-related antigen-2 induces progressive peripheral vasculopathy in mice closely resembling human systemic sclerosis. Circulation 2009, 120(23):2367–2376. This study showed that mice overexpressing Fra-2 show both fibrotic and vascular characteristics of SSc. In addition, the study showed that Fra-2 is overexpressed in SSc ECs. The authors also demonstrated that blocking Fra-2 in ECs enhances VEGF-mediated angiogenesis in vitro. In all, this study established Fra-2 as an angiogenic transcription factor and demonstrated that Fra-2 transgenic mice may be an excellent model of SSc. PubMedCrossRefGoogle Scholar
  46. 46.
    Reich N, Maurer B, Akhmetshina A, et al. The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis Rheum. 2010;62(1):280–90.PubMedCrossRefGoogle Scholar
  47. 47.
    Spyropoulos DD, Pharr PN, Lavenburg KR, et al. Hemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor. Mol Cell Biol. 2000;20(15):5643–52.PubMedCrossRefGoogle Scholar
  48. 48.
    Liu F, Walmsley M, Rodaway A, Patient R. Fli1 acts at the top of the transcriptional network driving blood and endothelial development. Curr Biol. 2008;18(16):1234–40.PubMedCrossRefGoogle Scholar
  49. 49.
    Kubo M, Czuwara-Ladykowska J, Moussa O, et al. Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin. Am J Pathol. 2003;163(2):571–81.PubMedCrossRefGoogle Scholar
  50. 50.
    •• Asano Y, Stawski L, Hant F et al.: Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy. Am J Pathol 2010, 176(4):1983–1998. This novel study expanded on the finding that Fli1 is decreased in SSc ECs by generating mice with Fli1 conditionally knocked out on ECs. The mice exhibited an “SSc-like” phenotype and implicated a role for Fli1 in the vascular pathology of SSc. In addition, the murine model has the potential to serve as a model of SSc vascular disease. PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Department of Veterans AffairsVA Medical ServiceAnn ArborUSA
  3. 3.Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborUSA

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