Gastroenterology
Volume 134, Issue 1 , Pages 215-225 , January 2008

Roles of Calcitonin Gene–Related Peptide in Maintenance of Gastric Mucosal Integrity and in Enhancement of Ulcer Healing and Angiogenesis

  • Takashi Ohno

      Affiliations

    • Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • Isehara Kyodo Hospital, Isehara, Kanagawa
    • ,
  • Youichiro Hattori

      Affiliations

    • Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • Department of Molecular Pharmacology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa
    • ,
  • Rie Komine

      Affiliations

    • Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • ,
  • Takako Ae

      Affiliations

    • Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • Department of Molecular Pharmacology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa
    • ,
  • Sumito Mizuguchi

      Affiliations

    • Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • Department of Molecular Pharmacology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa
    • ,
  • Katsuharu Arai

      Affiliations

    • Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • ,
  • Takeo Saeki

      Affiliations

    • Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • ,
  • Tatsunori Suzuki

      Affiliations

    • Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • Department of Molecular Pharmacology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa
    • ,
  • Kanako Hosono

      Affiliations

    • Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • ,
  • Izumi Hayashi

      Affiliations

    • Department of Pathophysiology, Nippon Pharmaceutical University, Ina, Saitama, Tokyo, Japan
    • ,
  • Yoshio Oh–Hashi

      Affiliations

    • Isehara Kyodo Hospital, Isehara, Kanagawa
    • ,
  • Yukiko Kurihara

      Affiliations

    • Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, Tokyo University, Tokyo, Japan
    • ,
  • Hiroki Kurihara

      Affiliations

    • Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, Tokyo University, Tokyo, Japan
    • ,
  • Kikuko Amagase

      Affiliations

    • Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
    • ,
  • Susumu Okabe

      Affiliations

    • Department of Pharmacology, Doshisha Women’s College, Kyoto, Japan
    • ,
  • Katsunori Saigenji

      Affiliations

    • Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • ,
  • Masataka Majima

      Affiliations

    • Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa
    • Department of Molecular Pharmacology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa
    • Corresponding Author InformationAddress requests for reprints to: Masataka Majima, MD, Kitasato University School of Medicine, Kanagawa, 228-8555, Japan. fax: (81) 42-778-7604.

Received 6 November 2006 ,Accepted 20 September 2007.

References 

  1. Oh-hashi Y, Shindo T, Kurihara Y, et al. Elevated sympathetic nervous activity in mice deficient in alphaCGRP. Circ Res. 2001;89:983–990
  2. Pinto A, Sekizawa K, Yamaya M, et al. Effects of adrenomedullin and calcitonin gene–related peptide on airway and pulmonary vascular smooth muscle in guinea-pigs. Br J Pharmacol. 1996;119:1477–1483
  3. Holzer P. Neural emergency system in the stomach. Gastroenterology. 1998;114:823–839
  4. Green T, Dockray GJ. Calcitonin gene-related peptide and substance P in afferents to the upper gastrointestinal tract in the rat. Neurosci Lett. 1987;76:151–156
  5. Sharkey KA, Williams RG, Dockray GJ. Sensory substance P innervation of the stomach and pancreas (Demonstration of capsaicin-sensitive sensory neurons in the rat by combined immunohistochemistry and retrograde tracing). Gastroenterology. 1984;87:914–921
  6. Hayashi H, Ohno T, Nishiyama K, et al. Transient prevention of ethanol-induced gastric lesion by capsaicin due to release of endogenous calcitonin gene-related peptide in rats. Jpn J Pharmacol. 2001;86:351–354
  7. Boku K, Ohno T, Saeki T, et al. Adaptive cytoprotection mediated by prostaglandin I(2) is attributable to sensitization of CRGP-containing sensory nerves. Gastroenterology. 2001;120:134–143
  8. Arai K, Ohno T, Saeki T, et al. Endogenous prostaglandin I2 regulates the neural emergency system through release of calcitonin gene related peptide. Gut. 2003;52:1242–1249
  9. Saeki T, Ohno T, Kamata K, et al. Mild irritant prevents ethanol-induced gastric mucosal microcirculatory disturbances through actions of calcitonin gene-related peptide and PGI2 in rats. Am J Physiol Gastrointest Liver Physiol. 2004;286:G68–G75
  10. Ohno T, Katori M, Majima M, et al. Dilatation and constriction of rat gastric mucosal microvessels through prostaglandin EP2 and EP3 receptors. Aliment Pharmacol Ther. 1999;13:1243–1250
  11. Ohno T, Katori M, Nishiyama K, et al. Direct observation of microcirculation of the basal region of rat gastric mucosa. J Gastroenterol. 1995;30:557–564
  12. Ohno T, Katori M, Majima M, et al. Different responses of arterioles and venules in rat gastric mucosal microcirculation to endothelin-1 and endothelin-3. J Clin Gastroenterol. 1995;21(Suppl 1):S56–S65
  13. Ikeda Y, Hayashi I, Kamoshita E, et al. Host stromal bradykinin B2 receptor signaling facilitates tumor-associated angiogenesis and tumor growth. Cancer Res. 2004;64:5178–5185
  14. Majima M, Amano H, Hayashi I. Prostanoid receptor signaling relevant to tumor growth and angiogenesis. Trends Pharmacol Sci. 2003;24:524–529
  15. Katada J, Muramatsu M, Hayashi I, et al. Significance of vascular endothelial cell growth factor up-regulation mediated via a chymase-angiotensin-dependent pathway during angiogenesis in hamster sponge granulomas. J Pharmacol Exp Ther. 2002;302:949–956
  16. Kamoshita E, Ikeda Y, Fujita M, et al. Recruitment of a prostaglandin E receptor subtype, EP3-expressing bone marrow cells is crucial in wound-induced angiogenesis. Am J Pathol. 2006;169:1458–1472
  17. Amano H, Hayashi I, Endo H, et al. Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth. J Exp Med. 2003;197:221–232
  18. Majima M, Hayashi I, Muramatsu M, et al. Cyclooxygenase-2 enhances basic fibroblast growth factor-induced angiogenesis through the induction of vascular endothelial growth factor in rat sponge implants. Br J Pharmacol. 2000;130:641–649
  19. Majima M, Isono M, Ikeda Y, et al. Significant roles of inducible cyclooxygenase (COX)-2 in angiogenesis in rat sponge implants. Jpn J Pharmacol. 1997;75:105–114
  20. Okabe S, Amagase K. An overview of acetic acid ulcer models—the history and state of the art of peptic ulcer research. Biol Pharm Bull. 2005;28:1321–1341
  21. Wimalawansa SJ, Morris HR, Etienne A, et al. Isolation, purification and characterization of beta-hCGRP from human spinal cord. Biochem Biophys Res Commun. 1990;167:993–1000
  22. Wimalawansa SJ. Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. Endocr Rev. 1996;17:533–585
  23. Zhang L, Hoff AO, Wimalawansa SJ, et al. Arthritic calcitonin/alpha calcitonin gene-related peptide knockout mice have reduced nociceptive hypersensitivity. Pain. 2001;89:265–273
  24. Gangula PR, Zhao H, Supowit SC, et al. Increased blood pressure in alpha-calcitonin gene-related peptide/calcitonin gene knockout mice. Hypertension. 2000;35:470–475
  25. Lu JT, Son YJ, Lee J, et al. Mice lacking alpha-calcitonin gene-related peptide exhibit normal cardiovascular regulation and neuromuscular development. Mol Cell Neurosci. 1999;14:99–120
  26. Matuoka K, Tanaka M, Mitsui Y. Cultured rabbit gastric epithelial cells producing prostaglandin I2. Gastroenterology. 1983;84:498–505
  27. Ferreira SH, Moncada S, Vane JR. Prostaglandins and the mechanism of analgesia produced by aspirin-like drugs. Br J Pharmacol. 1973;49:86–92
  28. Hori Y, Katori M, Uchida Y, et al. Potentiation of bradykinin-induced nociceptive response by arachidonate metabolites in dogs. Eur J Pharmacol. 1986;132:47–52
  29. Tone Y, Inoue H, Hara S, et al. The regional distribution and cellular localization of mRNA encoding rat prostacyclin synthase. Eur J Cell Biol. 1997;72:268–277
  30. Oida H, Namba M, Sugimoto Y. In situ hybridization of studies of prostaglandin receptor mRNA expression in various mouse organs. Br J Pharmacol. 1995;116:2828–2837
  31. Gono Y, Ichikawa T, Hotta K, et al. Topographical distribution of neuropeptide-containing nerve fibers in the rat stomach: a quantitative analysis using antibodies against protein gene product 9.5 and gastric mucins. Biomed Res. 1998;19:357–368
  32. Saeki T, Ohno T, Boku K, et al. Mechanism of prevention by capsaicin of ethanol-induced gastric mucosal injury—a study in the rat using intravital microscopy. Aliment Pharmacol Ther. 2000;14(Suppl 1):135–144
  33. Ohno T, Katori M, Majima M, et al. Involvement of nitric oxide in endothelin 1–induced, but not in acetylcholine-induced arteriolar dilatation in rat gastric mucosal microcirculation. Microcirc Annu. 1995;11:103–104
  34. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–257
  35. Fan TP, Hu DE, Guard S, et al. Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by NK1 or interleukin-1 receptor antagonists. Br J Pharmacol. 1993;110:43–49
  36. Mizuno H, Sakamoto C, Matsuda K, et al. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology. 1997;112:387–397
  37. Amano H, Ando K, Minamida S, et al. Adenylate cyclase/protein kinase A signaling pathway enhances angiogenesis through induction of vascular endothelial growth factor in vivo. Jpn J Pharmacol. 2001;87:181–188

 The authors thank Michiko Ogino and Osamu Katsumata for technical assistance. This work was supported by research grants (#12470529 and #12670094), by a High-tech Research Center grant, by an Academic Frontier Project grant, and by a grant from The 21st Century COE Program, from the Ministry of Education, Culture, Sports, Science and Technology. This study was also supported by an Integrative Research Program of the Graduate School of Medical Science, Kitasato University. We are also grateful to Mr. C.W.P. Reynolds for linguistic assistance in the preparation of the manuscript.

PII: S0016-5085(07)01798-2

doi: 10.1053/j.gastro.2007.10.001

Gastroenterology
Volume 134, Issue 1 , Pages 215-225 , January 2008

Article Tools

* Image Usage & Resolution