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

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• 作者：Takehito Sato (1) (2) r> Hideki Amano (1) r> Yoshiya Ito (3) r> Koji Eshima (4) r> Tsutomu Minamino (2) r> Takako Ae (2) r> Chikatoshi Katada (2) r> Takashi Ohno (5) r> Kanako Hosono (1) r> Tatsunori Suzuki (1) r> Masabumi Shibuya (6) r> Wasaburo Koizumi (2) r> Masataka Majima (1) r>
• 关键词：Gastric ulcer ; Bone marrow ; VEGFR1 ; CXCR4 ; EGF
• 刊名：Journal of Gastroenterology
• 出版年：2014
• 出版时间：March 2014
• 年：2014
• 卷：49
• 期：3
• 页码：455-469
• 全文大小：3,746 KB
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• 作者单位：Takehito Sato (1) (2) r> Hideki Amano (1) r> Yoshiya Ito (3) r> Koji Eshima (4) r> Tsutomu Minamino (2) r> Takako Ae (2) r> Chikatoshi Katada (2) r> Takashi Ohno (5) r> Kanako Hosono (1) r> Tatsunori Suzuki (1) r> Masabumi Shibuya (6) r> Wasaburo Koizumi (2) r> Masataka Majima (1) r>r>1. Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami, Sagamihara, Kanagawa, 252-0374, Japan r> 2. Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa, Japan r> 3. Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan r> 4. Department of Immunology, Kitasato University School of Medicine, Kanagawa, Japan r> 5. Isehara Kyodo Hospital, Isehara, Japan r> 6. Department of Research and Education, Jobu University, Takasaki, Japan r>
• ISSN：1435-5922

文摘

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??/sup>). Bone marrow transplantation into irradiated WT mice was carried out using bone marrow cells isolated from WT and VEGFR1 TK??/sup> mice. Results Ulcer healing was delayed in VEGFR1 TK??/sup> 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??/sup> mice, ulcer healing and angiogenesis were suppressed, and this was associated with reduced recruitment of bone marrow cells to ulcer granulation tissue. VEGFR1 TK??/sup> 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.