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Vascular endothelial growth factor receptor 1 signaling facilitates gastric ulcer healing and angiogenesis through the upregulation of epidermal growth factor expression on VEGFR1+CXCR4+ cells recruited from bone marrow

  • Original Article—Alimentary Tract
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Abstract

Background

Angiogenesis is essential for gastric ulcer healing. Recent results suggest that vascular endothelial growth factor receptor 1 (VEGFR1), which binds to VEGF, promotes angiogenesis. In the present study, we investigated the role of VEGFR1 signaling in gastric ulcer healing and angiogenesis.

Methods

Gastric ulcers were induced by serosal application of 100 % acetic acid in wild-type (WT) and tyrosine kinase-deficient VEGFR1 mice (VEGFR1 TK−/−). Bone marrow transplantation into irradiated WT mice was carried out using bone marrow cells isolated from WT and VEGFR1 TK−/− mice.

Results

Ulcer healing was delayed in VEGFR1 TK−/− mice compared to WT mice and this was accompanied by decreased angiogenesis, as evidenced by reduced mRNA levels of CD31 and decreased microvessel density. Recruitment of cells expressing VEGFR1 and C-X-C chemokine receptor type 4 (CXCR4) was suppressed and epidermal growth factor (EGF) expression in ulcer granulation tissue was attenuated. Treatment of WT mice with neutralizing antibodies against VEGF or CXCR4 also delayed ulcer healing. In WT mice transplanted with bone marrow cells from VEGFR1 TK−/− mice, ulcer healing and angiogenesis were suppressed, and this was associated with reduced recruitment of bone marrow cells to ulcer granulation tissue. VEGFR1 TK−/− bone marrow chimeras also exhibited downregulation of EGF expression on CXCR4+VEGFR1+ cells recruited from the bone marrow into ulcer lesions.

Conclusion

VEGFR1-mediated signaling plays a critical role in gastric ulcer healing and angiogenesis through enhanced EGF expression on VEGFR1+CXCR4+ cells recruited from the bone marrow into ulcer granulation tissue.

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Acknowledgments

We thank Michiko Ogino, Kyoko Yoshikawa, and Mieko Hamano for their technical assistance. This work was supported by research grants (nos. 21791331 and 21390072) from the High-Tech Research Center grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan. This study was also supported by an Integrative Research Program of the Graduate School of Medical Science, Kitasato University.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami, Sagamihara, Kanagawa, 252-0374, Japan

    Takehito Sato, Hideki Amano, Kanako Hosono, Tatsunori Suzuki & Masataka Majima

  2. Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa, Japan

    Takehito Sato, Tsutomu Minamino, Takako Ae, Chikatoshi Katada & Wasaburo Koizumi

  3. Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan

    Yoshiya Ito

  4. Department of Immunology, Kitasato University School of Medicine, Kanagawa, Japan

    Koji Eshima

  5. Isehara Kyodo Hospital, Isehara, Japan

    Takashi Ohno

  6. Department of Research and Education, Jobu University, Takasaki, Japan

    Masabumi Shibuya

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  1. Takehito Sato
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Correspondence to Masataka Majima.

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Sato, T., Amano, H., Ito, Y. et al. Vascular endothelial growth factor receptor 1 signaling facilitates gastric ulcer healing and angiogenesis through the upregulation of epidermal growth factor expression on VEGFR1+CXCR4+ cells recruited from bone marrow. J Gastroenterol 49, 455–469 (2014). https://doi.org/10.1007/s00535-013-0869-z

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