Basic–Alimentary TractRoles of Calcitonin Gene–Related Peptide in Maintenance of Gastric Mucosal Integrity and in Enhancement of Ulcer Healing and Angiogenesis
Section snippets
Animals
A strain of 8-week-old male CGRP receptor knockout mice (CGRP−/−)1 and their wild-type counterparts (WT, male) were used. To estimate immunohistochemical localization of CGRP in gastric mucosa, we isolated gastric specimens under normal conditions from WT mice, and the sections were stained with rabbit polyclonal antibody against CGRP (Cambridge Research Biochemicals, Northwich, UK) as described earlier. All mice were kept in a room maintained at a constant temperature (25° ± 1°C) and humidity
Localization of CGRP in Normal Gastric Mucosa and Reduced Gastric Contents of CGRP in CGRP−/−
In WT, immunoreactive CGRP was present in the nerve fibers of the gastric mucosa (Figure 1A) and submucosal layer (Figure 1B), whereas the immunoreactive CGRP was hardly detected in the gastric mucosa in CGRP−/− (data not shown). When CGRP contents in the stomach were determined by enzyme immunoassay in WT, CGRP detected was 13.0 ± 2.1 pg/mg wet tissue of stomach (Figure 1C). By contrast, CGRP content in CGRP−/− was below the detection limits (0.05 pg/mg wet tissue of stomach) (Figure 1C).
Lack of Capsaicin-Induced Gastric Mucosal Protective Actions Against Ethanol in CGRP−/−
As
Discussion
CGRP is a 37-amino acid vasoactive neuropeptide produced by tissue-specific alternative splicing of the primary transcript of the calcitonin/CGRP gene.21 Although the biologic properties of CGRP have been studied,22 its pathophysiologic roles are not fully elucidated. Some groups, including ours, have developed CGRP−/− using gene-targeting strategies.1, 23, 24, 25 Little was examined in CGRP-null mice in terms of the contribution of CGRP to gastric mucosal protection, although cardiovascular
References (37)
Neural emergency system in the stomach
Gastroenterology
(1998)- et al.
Calcitonin gene-related peptide and substance P in afferents to the upper gastrointestinal tract in the rat
Neurosci Lett
(1987) - et al.
Sensory substance P innervation of the stomach and pancreasDemonstration of capsaicin-sensitive sensory neurons in the rat by combined immunohistochemistry and retrograde tracing
Gastroenterology
(1984) - 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) - et al.
Adaptive cytoprotection mediated by prostaglandin I(2) is attributable to sensitization of CRGP-containing sensory nerves
Gastroenterology
(2001) - et al.
Prostanoid receptor signaling relevant to tumor growth and angiogenesis
Trends Pharmacol Sci
(2003) - et al.
Recruitment of a prostaglandin E receptor subtype, EP3-expressing bone marrow cells is crucial in wound-induced angiogenesis
Am J Pathol
(2006) - et al.
Isolation, purification and characterization of beta-hCGRP from human spinal cord
Biochem Biophys Res Commun
(1990) - et al.
Arthritic calcitonin/alpha calcitonin gene-related peptide knockout mice have reduced nociceptive hypersensitivity
Pain
(2001) - et al.
Mice lacking alpha-calcitonin gene-related peptide exhibit normal cardiovascular regulation and neuromuscular development
Mol Cell Neurosci
(1999)
Cultured rabbit gastric epithelial cells producing prostaglandin I2
Gastroenterology
Potentiation of bradykinin-induced nociceptive response by arachidonate metabolites in dogs
Eur J Pharmacol
Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice
Gastroenterology
Adenylate cyclase/protein kinase A signaling pathway enhances angiogenesis through induction of vascular endothelial growth factor in vivo
Jpn J Pharmacol
Elevated sympathetic nervous activity in mice deficient in alphaCGRP
Circ Res
Effects of adrenomedullin and calcitonin gene–related peptide on airway and pulmonary vascular smooth muscle in guinea-pigs
Br J Pharmacol
Endogenous prostaglandin I2 regulates the neural emergency system through release of calcitonin gene related peptide
Gut
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
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2020, European Journal of PharmacologyCitation Excerpt :Furthermore, exogenous CGRP promotes HUVEC secretion of vascular endothelial growth factor (VEGF) in vitro (Lv et al., 2019), which is a key player in the formation of blood vessels and endothelial proliferation (Cai et al., 2006). In vivo, endogenous CGRP has also been found to have proangiogenic activity (Ohno et al., 2008). In CGRP KO mice, basal cardiac microvessel density is decreased in response to transverse aortic constriction-induced cardiac pressure overload leading to cardiac hypertrophy, cardiomyocyte cell death, and eventually, decreased survival rate for the CGRP KO mice, illustrating that CGRP may play a key role in microvascular development (Li et al., 2013).
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2019, Trends in Pharmacological SciencesCitation Excerpt :The development of chronic inflammation is highly dependent on angiogenesis, which has been particularly observed during chronic proliferative inflammation in subcutaneous surgical sponge implants, a process regulated by endogenous CGRP derived from neuronal systems [4]. VEGF is an important downstream molecule of CGRP receptor signaling, and its upregulation was also observed during healing of skin wounds [57] and gastric ulcer healing [5], both highly dependent on angiogenesis. Healing of acetic acid-induced ulcers is markedly delayed in CGRP-KO animals with reduced angiogenesis in the granulation tissues, which is new connective tissue formed at the base of ulcers [5].
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.