title: 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.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami, Sagamihara, Kanagawa, 252-0374, Japan.
authors: Takehito
authors: T
authors: Sato
authors: Hideki
authors: H
authors: Amano
authors: Yoshiya
authors: Y
authors: Ito
authors: Koji
authors: K
authors: Eshima
authors: Tsutomu
authors: T
authors: Minamino
authors: Takako
authors: T
authors: Ae
authors: Chikatoshi
authors: C
authors: Katada
authors: Takashi
authors: T
authors: Ohno
authors: Kanako
authors: K
authors: Hosono
authors: Tatsunori
authors: T
authors: Suzuki
authors: Masabumi
authors: M
authors: Shibuya
authors: Wasaburo
authors: W
authors: Koizumi
authors: Masataka
authors: M
authors: Majima
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D013276:Stomach Ulcer / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*
chemical_list: C514936:CXCR4 protein, mouse; D019718:Receptors, CXCR4; D004815:Epidermal Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1
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