Skip to main content
SpringerLink
Log in

Elevated Serum Vascular Endothelial Growth Factor in Children and Young Adults with Crohn's Disease

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Vascular endothelial growth factor (VEGF) is acytokine released by fibroblasts, epithelial cells, andleukocytes that potentiates vascular permeability andgrowth of new capillaries. Because of these multiple effects, VEGF has been postulated to play arole in the pathogenesis of autoimmune disease, as wellas in wound healing. We hypothesized that VEGF waspotentially important in mediating the vascularpermeability and angiogenesis seen in Crohn's disease, andtherefore that VEGF would be increased in the serum ofchildren with Crohn's disease. Serum was obtained from73 children and young adults with Crohn's disease, 47 with ulcerative colitis, and 29 controls.VEGF levels were measured by enzyme-linked immunosorbentassay. Mean VEGF levels were significantly higher inpatients with Crohn's disease (436.4 ± 37.2pg/ml) than in ulcerative colitis (306 ± 41.1pg/ml) or control (167.8 ± 29.6 pg/ml) patients.Serum VEGF also correlated significantly with diseaseactivity, being elevated in patients withmoderate/severe Crohn's disease and ulcerative colitis. Weconclude that serum VEGF is released by inflamed tissuesin children with Crohn's disease. This multifunctionalcytokine could promote inflammation by increasing vascular permeability or promote wound healingby mediating capillary growth.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Schreiber S, Raedler A, Stenson W, McDermott R: The role of the mucosal immune system in inflammatory bowel disease. Gastroenterol Clin North Am 21:451–502, 1992

    Google Scholar 

  2. Sartor R: Current concepts in the etiology and pathogenesis of ulcerative colitis and Crohn's disease. Gastroenterol Clin North Am 24:475–507, 1995

    Google Scholar 

  3. Murch S, Lamkin V, Savage M, Walker-Smith J, MacDonald T: Serum concentrations of tumour necrosis factor alpha in childhood chronic inflammatory bowel disease. Gut 32:913–917, 1991

    Google Scholar 

  4. Wakefield A, Dhillon A, Rowles P, Sawyer A, Pittilo R, Lewis A, Pounder R: Pathogenesis of Crohn's disease: Multifocal gastrointestinal infarction. Lancet 2:1057–1062, 1989

    Google Scholar 

  5. Folkman J: Clinical applications of research on angiogenesis. N Engl J Med 333:1757–1763, 1995

    Google Scholar 

  6. Schweigerer L, Fotsis T: Angiogenesis and angiogenesis inhibitors in pediatric diseases. Eur J Pediatr 151:472–476, 1992

    Google Scholar 

  7. Risau W, Flamme I: Vasculogenesis. Annu Rev Cell Biol 11:73–91, 1995

    Google Scholar 

  8. Ferrara N: Vascular endothelial growth factor. Eur J Cancer 32A(14):2413–2422, 1996

    Google Scholar 

  9. Fava R, Olsen N, Spencer-Green G, Yeo K, Yeo T, Berse B, Jackman R, Senger D, Dvorak H, Brown L: Vascular permeability factor/endothelial growth factor (VPF:VEGF): Accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med 180:341–346, 1994

    Google Scholar 

  10. Nagashima M, Yoshino S, Ishiwata T, Asano G: Role of vascular endothelial growth factor in angiogenesis of rheumatoid arthritis. J Rheumatol 22:1624–1630, 1995

    Google Scholar 

  11. Dvorak H, Brown L, Detmar M, Dvorak A: Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039, 1995

    Google Scholar 

  12. Berse B, Brown L, vandeWater L, Dvorak H, Senger D: Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell 3:211–220, 1992

    Google Scholar 

  13. Brown L, Berse B, Jackman R, Tognazzi K, Manseau E, Senger D, Dvorak H: Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res 53:4727–4735, 1993

    Google Scholar 

  14. Bousvaros A, Zurakowski D, Fishman S, Keough K, Law T, Sun C, Leichtner A: Serum basicfibroblast growth factor in pediatric Crohn's disease: Implications for wound healing. Dig Dis Sci 42:378–386, 1997

    Google Scholar 

  15. Hyams J, Ferry G, Mandel F, Gryboski J, Kibort P, Kirschner B, Griffiths A, Katz A, Granel R, Boyle J, Michener W, Levy J, Lesser M: Development and validation of a pediatric Crohn's disease activity index. J Pediatr Gastroenterol Nutr 12:439–447, 1991

    Google Scholar 

  16. Kozarek R, Patterson D, Gelfand M, Botoman V, Ball T, Wilske K: Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med 110:353–356, 1989

    Google Scholar 

  17. Shapiro S, Wilk M: An analysis of variance test for normality (complete samples). Biometrika 52:591–611, 1965

    Google Scholar 

  18. Miller R: Simultaneous Statistical Inference, 2nd ed. New York, Springer-Verlag, 1981, pp 90–93

    Google Scholar 

  19. Pertovaara L, Kaipainen A, Mustonen T, Orpana A, Ferrara N, Saksela O, Alitalo K: Vascular endothelial growth factor is induced in response to transforming growth factor beta in fibroblastic and epithelial cells. J Biol Chem 269:6271–6274, 1994

    Google Scholar 

  20. Horiuchi T, Weller P: Expression of vascular endothelial growth factor by human eosinophils: Upregulation by granulocyte macrophage colony stimulating factor and interleukin-5. Am J Respir Cell Mol Biol 17:70–77, 1997

    Google Scholar 

  21. Taichman N, Young S, Cruchley A, Taylor P, Paleolog E: Human neutrophils secrete vascular endothelial growth factor. J Leukocyte Biol 62:397–400, 1997

    Google Scholar 

  22. Cohen T, Nahari D, Cerem L, Neufeld G, Levi B: Interleukin-6 induces the expression of vascular endothelial growth factor. J Biol Chem 271:736–741, 1996

    Google Scholar 

  23. Yoshida S, Ono M, Shono T, izumi H, Ishibashi T, Suzuki H, Kuwano M: Involvement of interleukin-8, vascular endothelial growth factor, and basicfibroblast growth factor in tumornecrosis factor alpha dependent angiogenesis. Mol Cell Biol 17:4015–4023, 1997

    Google Scholar 

  24. Waltenberger J, Mayr U, Pentz S, Hombach V: Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia. Circulation 94:1647–1654, 1996

    Google Scholar 

  25. Enholm B, Paavonen K, Ristimaki A, Kumar V, Gunji Y, Klefstrom J, Kivinen L, Laiho M, Olofsson B, Joukov V, Eriksson U, Alitalo K: Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins, and hypoxia. Oncogene 14:2475–2483, 1997

    Google Scholar 

  26. Ferrara N, Keyt B: Vascular endothelial growth factor: Basic biology and clinical applications, Regulation of Angiogenesis. I Goldberg, E Rosen (eds). Basel, Switzerland, Birkhauser Verlag, 1997, pp 209–232

    Google Scholar 

  27. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea K, Powell-Braxton L, Hillan K, Moore M: Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439–442, 1996

    Google Scholar 

  28. Torry D, Torry R: Angiogenesis and the expression of vascular endothelial growth factor in endometrium and placenta. Am J Reprod Immunol 37:21–29, 1997

    Google Scholar 

  29. Bates D, Curry F: Vascular endothelial growth factor increases microvascular permeability via a calcium dependent pathway. Am J Physiol 273:H687–H694, 1997

    Google Scholar 

  30. Dvorak H, Harvey V, Estrella P, Brown L, McDonagh J, Dvorak A: Fibrin containing gels induce angiogenesis. Implications for tumor stroma generation and wound healing. Lab Invest 57:673–686, 1987

    Google Scholar 

  31. Aiello L, Avery R, Arrigg P, Keyt B, Jampel H, Shah S, Pasquale L, Thieme H, Iwamoto M, Park J, Nguyen H, Aiello L, Ferrara N, King G: Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487, 1994

    Google Scholar 

  32. Dvorak H, Sioussat T, Brown L, Berse B, Nagy J, Sotrel A, Manseau E, VanDeWater L, Senger D: Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. J Exp Med 174:1275–1278, 1991

    Google Scholar 

  33. Yoshiji H, Harris S, Thorgeirsson U: Vascular endothelial growth factor is essential for initial but not continued in vivo growth of human breast carcinoma cells. Cancer Res 57:3924–3928, 1997

    Google Scholar 

  34. Dirix L, Vermeulen P, Pawinski A, Prove A, Benoy I, De-Pooter C, Martin M, VanOosterom A: Elevated levels of the angiogenic cytokines basicfibroblast growth factor and vascular endothelial growth factor in the sera of cancer patients. Br J Cancer 76:238–243, 1997

    Google Scholar 

  35. Akiyoshi F, Sata M, Suzuki H, Uchimura Y, Mitsuyama K, Matsuo K, Tanikawa K: Serum vascular endothelial growth factor levels in various liver diseases. Dig Dis Sci 43:41–45, 1998

    Google Scholar 

  36. Griga T, Winse A, Tromm A, May B: Increased serum levels of vascular endothelial growth factor in patients with inflammatory bowel disease. Gastroenterology 114:A988, 1998

    Google Scholar 

  37. Takahashi M, Kawabe T, Ogura K, Maeda S, Mikami Y, Kaneko N, Terano A, Omata M: Expression of vascular endothelial growth factor at the human gastric ulcer margin and in cultured gastricfibroblasts: A new angiogenic factor for gastric ulcer healing. Biochem Biophys Res Commun 234:493–498, 1997

    Google Scholar 

  38. Ibukiyama C: Angiogenesis. Angiogenic therapy usingfibroblast growth factors and vascular endothelial growth factors for ischemic vascular lesions. Jpn Heart J 37:285–300, 1996

    Google Scholar 

  39. Asahara T, Bauters C, Zheng L, Takeshita S, Bunting S, Ferrara N, Symes J, Isner J: Synergistic effect of vascular endothelial growth factor and basicfibroblast growth factor on angiogenesis in vivo. Circulation 92(suppl 9):II365–371, 1995

    Google Scholar 

  40. Proujansky R, Carpenter A: Soluble interleukin-2 receptor as a marker of lymphocyte activation in childhood Crohn's disease. J Pediatr Gastroenterol Nutr 13:277–284, 1991

    Google Scholar 

  41. Hyams J, Fitzgerald J, Treem W, Wyzga N, Kreutzer D: Relationship of functional and antigenic interleukin-6 to disease activity in inflammatory bowel disease. Gastroenterology 104:1285–1292, 1993

    Google Scholar 

  42. Bross D, Leichtner A, Zurakowski D, Law T, Bousvaros A: Elevation of se rum interleukin-6 but not serum interleukin 2 receptor in children with Crohn's disease. J Pediatr Gastroenterol Nutr 23:164–171, 1996

    Google Scholar 

Download references

Authors
  1. Athos Bousvaros
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan Leichtner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Zurakowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeanie Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Terry Law
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karen Keough
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Steven Fishman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bousvaros, A., Leichtner, A., Zurakowski, D. et al. Elevated Serum Vascular Endothelial Growth Factor in Children and Young Adults with Crohn's Disease. Dig Dis Sci 44, 424–430 (1999). https://doi.org/10.1023/A:1026635308127

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026635308127

Search

Navigation