Clinical associations of vascular endothelial growth factor in patients with systemic sclerosis

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Aim: To assess serum levels of vascular endothelial growth factor (VEGF) and its clinical correlates in patients with systemic sclerosis (SSc). Materials and methods: Forty six (46) patients with SSc aged from 19 to 77 years (median, 50 years), with duration of the disease from 0.5 to 24 years (median, 7 years) were recruited into the study. There were equal numbers of the patients with limited (LSSc) and diffuse (DSSc) types of the disease (23 patients in each group, or 50%). All patients underwent clinical examination, including measurement of the forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO) and pulmonary artery systolic pressure (PASP). Serum VEGF-A levels were determined by immunoenzyme assay in the patients and in 20 healthy controls. Results: VEGF levels in the healthy individuals were in the range from 0.2 to 264 pg/mL (median, 90.2). In SSc patients they varied from 0.02 to 1034.2 pg/mL (median, 147.2), with mean VEGF levels being over 2-fold higher than that in the control group (212.35 ± 253.93 and 97.74 ± 71.46 pg/mL, respectively; p = 0.032). DSSc patients had VEGF levels of 0.02 to 599.8 pg/mL (median, 93.6), whereas in LSSc they were from 0.02 to 1034.2 pg/mL (median, 162.4). Mean VEGF level in LSSc was higher than in DSSc (267.11 ± 268.74 vs 120.4 ± 141.09 pg/mL, respectively; p = 0.012). Current or past digital ulcers were found in 19 (41%) of all patients. Mean VEGF level in the patients with digital ulcers was higher than in those without ulcers; however, the difference was not statistically significant. PASP exceeded 30 mm Hg in 19 (43%) of the patients. VEGF levels in the patients with PASP of less than 30 mm Hg and ≥ 31 mm Hg were in the range of 0.02 to 363.6 pg/mL (median, 79.6) and 0.2–1034.2 pg/mL (median, 222.3), respectively. Mean VEGF level in the patients with high PASP was significantly higher than that in the patients with normal PASP (р = 0.0042). In the patients with DLCO ≥ 50% and < 50% serum VEGF levels were found to be 0.02 to 599.8 pg/mL (median, 59.75) and 0.02 to 1034.2 pg/mL (median, 195.9), respectively. Mean VEGF levels in the patients with DLCO of less than 50% was significantly higher than in the patients with DLCO of 50% and above (364.2 ± 381.95 and 128.55 ± 142.7, respectively, р = 0.034). FVC was decreased (< 80% of predicted) in 11 (26%) of 43 patients. Mean VEGF levels in the patients with low FVC was higher than in those with normal FVC, although the difference was non-significant. There was a moderate direct association between VEGF levels and PASP values (R = 0.4; p = 0.007). Also, a trend towards an inverse correlation between DLCO and VEGF levels was observed, which was however non-significant (R = -0.28; р = 0.07). Conclusion: A significant proportion of SSc patients have high serum VEGF levels. A close association with some clinical correlates indicates a pathogenetic role of VEGF in SSc. Further studies are necessary to clarify the precise contribution of VEGF into SSc pathophysiology.

About the authors

R. T. Alekperov

V.A. Nasonova Research Institute of Rheumatology

Author for correspondence.
Email: ralekperov@list.ru
MD, PhD, Senior Research Fellow Россия

E. N. Alexandrova

V.A. Nasonova Research Institute of Rheumatology

Email: fake@neicon.ru
MD, PhD, Head of Laboratory of Immunology Россия

A. A. Novikov

V.A. Nasonova Research Institute of Rheumatology

Email: fake@neicon.ru
MD, PhD, Leading Research Fellow, Laboratory of Immunology Россия

L. P. Ananyeva

V.A. Nasonova Research Institute of Rheumatology

Email: fake@neicon.ru
MD, PhD, Professor, Head of Laboratory of Microcirculation Россия

References

  1. Guiducci S, Giacomelli R, Cerinic MM. Vascular complications of scleroderma. Autoimmun Rev. 2007;6(8):​520–3. doi: 10.1016/j.autrev.2006.12.006.
  2. Guiducci S, Distler O, Distler JH, Matucci-Cerinic M. Mechanisms of vascular damage in SSc – implications for vascular treatment strategies. Rheumatology (Oxford). 2008;47 Suppl 5:v18–20. doi: 10.1093/rheumatology/ken267.
  3. Cutolo M, Sulli A, Pizzorni C, Accardo S. Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis. J Rheumatol. 2000;27(1):​155–60.
  4. Алекперов РТ. Классификация микроангиопатии при системной склеродермии. Терапевтический архив. 2005;77(5):​52–6.
  5. Claman HN, Giorno RC, Seibold JR. Endothelial and fibroblastic activation in scleroderma. The myth of the "uninvolved skin". Arthritis Rheum. 1991;34(12):​1495–501. doi: 10.1002/art.1780341204.
  6. Freemont AJ, Hoyland J, Fielding P, Hodson N, Jayson MI. Studies of the microvascular endothelium in uninvolved skin of patients with systemic sclerosis: direct evidence for a generalized microangiopathy. Br J Dermatol. 1992;126(6):​561–8. doi: 10.1111/j.1365-2133.1992.tb00100.x.
  7. Mostmans Y, Cutolo M, Giddelo C, Decuman S, Melsens K, Declercq H, Vandecasteele E, De Keyser F, Distler O, Gutermuth J, Smith V. The role of endothelial cells in the vasculopathy of systemic sclerosis: A systematic review. Autoimmun Rev. 2017;16(8):​774–86. doi: 10.1016/j.autrev.2017.05.024.
  8. Birkenhäger R, Schneppe B, Röckl W, Wilting J, Weich HA, McCarthy JE. Synthesis and physiological activity of heterodimers comprising different splice forms of vascular endothelial growth factor and placenta growth factor. Biochem J. 1996;316(Pt 3):​703–7. doi: 10.1042/bj3160703.
  9. Distler O, Distler JH, Scheid A, Acker T, Hirth A, Rethage J, Michel BA, Gay RE, Müller-Ladner U, Matucci-Cerinic M, Plate KH, Gassmann M, Gay S. 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. doi: 10.1161/01.RES.0000134644.89917.96.
  10. Park JS, Park MC, Song JJ, Park YB, Lee SK, Lee SW. Application of the 2013 ACR/EULAR classification criteria for systemic sclerosis to patients with Raynaud's phenomenon. Arthritis Res Ther. 2015;17:77. doi: 10.1186/s13075-015-0594-5.
  11. Fleming JN, Nash RA, Mahoney WM Jr, Schwartz SM. Is scleroderma a vasculopathy? Curr Rheumatol Rep. 2009;11(2):​103–10.
  12. Hummers LK, Hall A, Wigley FM, Simons M. Abnormalities in the regulators of angiogenesis in patients with scleroderma. J Rheumatol. 2009;36(3):​576–82. doi: 10.3899/jrheum.080516.
  13. Maurer B, Distler A, Suliman YA, Gay RE, Michel BA, Gay S, Distler JH, Distler O. Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis. Ann Rheum Dis. 2014;73(10):​1880–7. doi: 10.1136/annrheumdis-2013-203535.
  14. Farouk HM, Hamza SH, El Bakry SA, Youssef SS, Aly IM, Moustafa AA, Assaf NY, El Dakrony AH. Dysregulation of angiogenic homeostasis in systemic sclerosis. Int J Rheum Dis. 2013;16(4):​448–54. doi: 10.1111/1756-185X.12130.
  15. Dunne JV, Keen KJ, Van Eeden SF. Circulating angiopoietin and Tie-2 levels in systemic sclerosis. Rheumatol Int. 2013;33(2):​475–84. doi: 10.1007/s00296-012-2378-4.
  16. Distler O, Del Rosso A, Giacomelli R, Cipriani P, Conforti ML, Guiducci S, Gay RE, Michel BA, Brühlmann P, Müller-Ladner U, Gay S, Matucci-Cerinic M. Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers. Arthritis Res. 2002;4(6):R11. doi: 10.1186/ar596.
  17. Choi JJ, Min DJ, Cho ML, Min SY, Kim SJ, Lee SS, Park KS, Seo YI, Kim WU, Park SH, Cho CS. Elevated vascular endothelial growth factor in systemic sclerosis. J Rheumatol. 2003;30(7):​1529–33.
  18. Kikuchi K, Kubo M, Kadono T, Yazawa N, Ihn H, Tamaki K. Serum concentrations of vascular endothelial growth factor in collagen diseases. Br J Dermatol. 1998;139(6):​1049–51.
  19. Hashimoto N, Iwasaki T, Kitano M, Ogata A, Hamano T. Levels of vascular endothelial growth factor and hepatocyte growth factor in sera of patients with rheumatic diseases. Mod Rheumatol. 2003;13(2):​129–34. doi: 10.3109/s10165-002-0211-8.
  20. Riccieri V, Stefanantoni K, Vasile M, Macrì V, Sciarra I, Iannace N, Alessandri C, Valesini G. Abnormal plasma levels of different angiogenic molecules are associated with different clinical manifestations in patients with systemic sclerosis. Clin Exp Rheumatol. 2011;29(2 Suppl 65):S46–52.
  21. Silva I, Almeida C, Teixeira A, Oliveira J, Vasconcelos C. Impaired angiogenesis as a feature of digital ulcers in systemic sclerosis. Clin Rheumatol. 2016;35(7):​1743–51. doi: 10.1007/s10067-016-3219-8.
  22. Гусева НГ. Системная склеродермия и псевдосклеродермические синдромы. М.: Медицина; 1993. 300 с.
  23. Mackiewicz Z, Sukura A, Povilenaité D, Ceponis A, Virtanen I, Hukkanen M, Konttinen YT. 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.
  24. Moritz F, Schniering J, Distler JHW, Gay RE, Gay S, Distler O, Maurer B. Tie2 as a novel key factor of microangiopathy in systemic sclerosis. Arthritis Res Ther. 2017;19(1):​105. doi: 10.1186/s13075-017-1304-2.
  25. Papaioannou AI, Zakynthinos E, Kostikas K, Kiropoulos T, Koutsokera A, Ziogas A, Koutroumpas A, Sakkas L, Gourgoulianis KI, Daniil ZD. Serum VEGF levels are related to the presence of pulmonary arterial hypertension in systemic sclerosis. BMC Pulm Med. 2009;9:18. doi: 10.1186/1471-2466-9-18.
  26. Pendergrass SA, Hayes E, Farina G, Lemaire R, Farber HW, Whitfield ML, Lafyatis R. Limited systemic sclerosis patients with pulmonary arterial hypertension show biomarkers of inflammation and vascular injury. PLoS One. 2010;5(8):e12106. doi: 10.1371/journal.pone.0012106.
  27. De Santis M, Ceribelli A, Cavaciocchi F, Crotti C, Massarotti M, Belloli L, Marasini B, Isailovic N, Generali E, Selmi C. Nailfold videocapillaroscopy and serum VEGF levels in scleroderma are associated with internal organ involvement. Auto Immun Highlights. 2016;7(1):​5. doi: 10.1007/s13317-016-0077-y.

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Copyright (c) 2017 Alekperov R.T., Alexandrova E.N., Novikov A.A., Ananyeva L.P.

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