Skip to main content
SpringerLink
Log in

Helicobacter pylori Down-Regulates the Receptors of Vascular Endothelial Growth Factor and Angiopoietin in Vascular Endothelial Cells: Implications in the Impairment of Gastric Ulcer Healing

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

Abstract

Once a peptic ulcer has developed, angiogenesis plays a critical role in its healing by enhancing the microcirculation in the healing site. Previous reports have shown that Helicobacter pylori infection delays the healing of chronic gastric ulcers. To elucidate the mechanism of delayed ulcer healing caused by H. pylori, we investigated the angiogenic phenotype and expression of receptors of angiogenic growth factors in vascular endothelial cells. After human umbilical vein endothelial cells (HUVECs) were treated with H. pylori water extract, angiogenic phenotype was determined by capillary tube formation and DNA synthesis assay. The expressions of the receptors of vascular endothelial growth factor and angiopoietin-1/-2 were assessed by reverse transcription-polymerase chain reaction and Western blot analysis in HUVECs and by double immunofluorescent staining in gastric mucosa. Angiogenic signaling in HUVECs was evaluated by using a quantitative intracellular calcium mobilization assay. H. pylori water extract significantly inhibited capillary tube formation and DNA synthesis and down-regulated the expressions of receptors of vascular endothelial growth factor and angiopoietin in HUVECs. H. pylori water extract suppressed vascular endothelial growth factor-induced intracellular calcium signaling in HUVECs. H. pylori may inhibit the expression of angiogenic growth factor receptors in vascular endothelial cells, which could explain, in part, the delayed healing of gastric ulcer by H. pylori.

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. Warren JR, Marshall BJ: Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1:1273–1275, 1983

    Google Scholar 

  2. Marshall BJ: Helicobacter pylori: The etiologic agent for peptic ulcer. JAMA 274:1064–1066, 1995

    Google Scholar 

  3. Hopkins RJ, Girardi LS, Turney EA: Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: A review. Gastroenterology 110:1244–1252, 1996

    Google Scholar 

  4. Hansing RL, D'Amico H, Levy M, Guillan RA: Prediction of Helicobacter pylori in gastric specimen by inflammatory and morphological histologic evaluation. Am J Gastroenterol 87:1125–1131, 1992

    Google Scholar 

  5. Kim JS, Jung HC, Kim JM, Song IS, Kim CY: Interleukin-8 expression by human neutrophils activated by Helicobacter pylori soluble proteins. Scand J Gastroenterol 33:1249–1255, 1998

    Google Scholar 

  6. Kim JS, Jung HC, Kim JM, Song IS, Kim CY: Helicobacter pylori water-soluble surface proteins activate human neutrophils and upregulate the expression of CXC chemokines. Dig Dis Sci 45:83–92, 2000

    Google Scholar 

  7. Kim JS, Kim JM, Jung HC, Song IS: Expression of cyclooxygenase-2 in human neutrophils activated by Helicobacter pylori watersoluble proteins: possible involvement of NF-?B and MAP kinase signaling pathway. Dig Dis Sci 46:2277–2284, 2001

    Google Scholar 

  8. Kim JS, Kim JM, Jung HC, Song IS, Kim CY: Inhibition of apoptosis in human neutrophils by Helicobacter pylori water-soluble surface proteins. Scand J Gastroenterol 36:589–600, 2001

    Google Scholar 

  9. Kim JS, Kim JM, Jung HC, Song IS: Caspase-3 activity and expression of Bcl-2 family in human neutrophils by Helicobacter pylori water-soluble proteins. Helicobacter 6:207–215, 2001

    Google Scholar 

  10. Battegay J: Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic approaches. J Mol Med 73:333–346, 1995

    Google Scholar 

  11. Szabo S, Khomenko T, Gombos Z, Deng XM, Jadus MR, Yoshida M: Transcription factors and growth factors in ulcer healing. Aliment Pharmacol Ther 14 (Suppl 1):33–43, 2000

    Google Scholar 

  12. Jones MK, Kawanaka H, Baatar D, Szabo IL, Tsugawa K, Pai R, Koh GY, Kim I, Sarfeh IJ, Tarnawski AS: Gene therapy for gastric ulcers with single local injection of naked DNA encoding VEGF and angiopoietin-1. Gastroenterology 121:1040–1047, 2001

    Google Scholar 

  13. Ernst H, Konturek PC, Hahn EG, Stosiek HP, Brzozowski T, Konturek SJ: Effect of local injection with basic fibroblast growth factor (BFGF) and neutralizing antibody to BFGF on gastric ulcer healing, gastric secretion, angiogenesis and gastric blood flow. J Physiol Pharmacol 52:377–390, 2001

    Google Scholar 

  14. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J: Vascular-specific growth factors and blood vessel formation. Nature 407:242–248, 2000

    Google Scholar 

  15. Ross JS, Bui HX, del Rosario A, Sonbati H, George M, Lee CY: Helicobacter pylori. Its role in the pathogenesis of peptic ulcer disease in a new animal model. Am J Pathol 141:721–727, 1992

    Google Scholar 

  16. Makino M, Koga T, Ito K, Kawada H, Tabata K: Delayed healing of chronic gastric ulcer after Helicobacter pylori infection in mice. J Pharm Pharmacol 50:943–948, 1998

    Google Scholar 

  17. Brzozowski T, Konturek PC, Konturek SJ, Kwiecien S, Pajdo R, Karczewska E, Stachura J, Hahn EG: Water extracts of Helicobacter pylori delay healing of chronic gastric ulcers in rats: role of cytokines and gastrin-somatostatin link. Digestion 60:22–33, 1999

    Google Scholar 

  18. Kurose I, Granger DN, Evans DJ Jr, Evans DG, Graham DY, Miyasaka M, Anderson DC, Wolf RE, Cepinskas G, Kvietys PR: Helicobacter pylori-induced microvascular protein leakage in rats: role of neutrophils, mast cells, and platelets. Gastroenterology 107:70–79, 1994

    Google Scholar 

  19. Kalia N, Jacob S, Brown NJ, Reed MW, Morton D, Bardhan KD: Studies on the gastric mucosal microcirculation. 2. Helicobacter pylori water soluble extracts induce platelet aggregation in the gastric mucosal microcirculation in vivo. Gut 41:748–752, 1997

    Google Scholar 

  20. Elizalde JI, Gomez J, Panes J, Lozano M, Casadevall M, Ramirez J, Pizcueta P, Marco F, Rojas FD, Granger DN, Pique JM: Platelet activation in mice and human Helicobacter pylori infection. J Clin Invest 100:996–1005, 1997

    Google Scholar 

  21. Kalia N, Jones C, Bardhan DK, Reed MW, Atherton JC, Brown NJ: Effects of genotypically different strains of Helicobacter pylori on human microvascular endothelial cells in vitro. Dig Dis Sci 46:54–61, 2001

    Google Scholar 

  22. Hudson N, Balsitis M, Everitt S, Hawkey CJ: Angiogenesis in gastric ulcers: impaired in patients taking non-steroidal anti-inflammatory drugs. Gut 37:191–194, 1995

    Google Scholar 

  23. Mai UEH, Perez-Perez GI, Allen JB, Wahl SM, Blaser MJ, Smith PD: Surface proteins from Helicobacter pylori exhibit chemotactic activity for human leukocytes and are present in gastric mucosa. J Exp Med 175:517–525, 1992

    Google Scholar 

  24. Gale NW, Yancopoulos GD: Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 13:1055–1066, 1999

    Google Scholar 

  25. Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM, Yancopoulos GD: Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 6:460–463, 2000

    Google Scholar 

  26. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD: Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60, 1997

    Google Scholar 

  27. Valter MM, Hugel A, Huang HJ, Cavenee WK, Wiestler OD, Pietsch T, Wernert N: Expression of the Ets-1 transcription facror in human astrocytomas is associated with Fms-like tyrosine kinase-1 (Flt-1)/vascular endothelial growth factor receptor-1 synthesis and neoangiogenesis. Cancer Res 59:5608–5614, 1999

    Google Scholar 

  28. Mandriota SJ, Menoud PA, Pepper MS: Transforming growth factor ?1 down-regulates vascular endothelial growth factor receptor 2/flk-1 expression in vascular endothelial cells. J Biol Chem 271:11500–11505, 1996

    Google Scholar 

  29. Semenza GL: Surviving ischemia: adaptive responses mediated by hypoxia-inducible factor 1. J Clin Invest 106:809–812, 2000

    Google Scholar 

  30. Yoshida N, Sugimoto N, Hirayama F, Nakamura Y, Ichikawa H, Naito Y, Yoshikawa T: Helicobacter pylori infection potentiates aspirin induced gastric mucosal injury in Mongolian gerbils. Gut 50:594–598, 2002

    Google Scholar 

  31. Huang JQ, Sridhar S, Hunt RH: Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet 359:14–22, 2002

    Google Scholar 

  32. Chan FK, To KF, Wu JC, Yung MY, Leung WK, Kwok T, Hui Y, Chan HL, Chan CS, Hui E, Woo J, Sung JJ: Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial. Lancet 359:9–13, 2002

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, and Clinical Research Institute, Seoul National University Hospital, Seoul, Korea

    Joo Sung Kim, Hyun Chae Jung & In Sung Song

  2. Department of Microbiology and Institute of Biomedical Science, Hanyang University College of Medicine, Seoul, Korea

    Jung Mogg Kim

Authors
  1. Joo Sung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jung Mogg Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hyun Chae Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. In Sung Song
    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

Kim, J.S., Kim, J.M., Jung, H.C. et al. Helicobacter pylori Down-Regulates the Receptors of Vascular Endothelial Growth Factor and Angiopoietin in Vascular Endothelial Cells: Implications in the Impairment of Gastric Ulcer Healing. Dig Dis Sci 49, 778–786 (2004). https://doi.org/10.1023/B:DDAS.0000030089.76514.e4

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:DDAS.0000030089.76514.e4

Search

Navigation