title: Vascular endothelial growth factor receptor-1 (VEGFR-1) signaling enhances angiogenesis in a surgical sponge model.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF)-A binds to both VEGF receptor (VEGFR)-1 and VEGFR-2, thereby promoting angiogenesis. It is widely accepted that VEGF-A, especially VEGFR-2, is a central player in angiogenesis, however the role of VEGFR-1 in angiogenesis remains unclear. The present study was conducted to examine the role of VEGFR-1 signaling in angiogenesis, using a quantitative in vivo angiogenesis model.
  
  
  METHODS
  Polyurethane sponge disks were implanted into dorsal subcutaneous tissue of mice. Angiogenesis was estimated by determining the number of CD31(+) vessels by immunohistochemical analysis. The expression of pro-angiogenic factors was quantified by reverse transcription quantitative polymerase chain reaction.
  
  
  RESULTS
  Compared to control IgG-treated mice, the number of CD31(+) vessels in the sponge implant was significantly suppressed in anti-VEGF-A neutralizing antibody-treated mice. CD31(+) vessel counts were suppressed in VEGFR-1 tyrosine kinase knockout (TKKO) mice, at the same level as in VEGFR-2 tyrosine kinase inhibitor (ZD6474)-treated mice compared to wild-type (WT) mice. The accumulation of VEGFR-1(+) cells in granulation tissue was significantly suppressed in VEGFR-1 TKKO mice compared to WT mice. In addition, expression of the pro-angiogenic growth factors, VEGF-A, matrix metalloproteinase-2, interleukin-6, and basic fibroblast growth factor in granulation tissue was suppressed in VEGFR-1 TKKO mice. A bone marrow (BM) transplantation experiment showed that the number of VEGFR-1(+) BM-derived cells and angiogenesis were significantly suppressed in VEGFR-1 TKKO mice transplanted with green fluorescent protein (GFP)(+) VEGFR-1 TKKO BM compared to WT mice transplanted with GFP(+) WT BM.
  
  
  CONCLUSIONS
  These results suggest that the VEGFR-1 tyrosine kinase signaling has an effect on angiogenesis. A selective VEGFR-1 agonist/antagonist could be a candidate therapeutic agent to control angiogenesis with recruitment of BM cells.
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan; Department of Plastic and Aesthetic Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Amano
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Plastic and Aesthetic Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kashiwagi
authors.affiliation: Department of Plastic and Aesthetic Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Department of Plastic and Aesthetic Surgery, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Takeda
authors.affiliation: Gakubunkan Institute of Physiology and Medicine, Jobu University, Tokyo, Japan.
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.affiliation: Department of Microbiology, Kitasato University School of Allied Health Science, Kanagawa, Japan.
authors.forename: Hidero
authors.initials: H
authors.lastname: Kitasato
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan. Electronic address: mmajima@med.kitasto-u.ac.jp.
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001853:Bone Marrow / Q000473:pathology; D002452:Cell Count; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006097:Granulation Tissue / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D015503:Surgical Sponges; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D015850:Interleukin-6; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D020778:Matrix Metalloproteinase 2
keywords: Angiogenesis; Bone marrow-derived cells; Granulation tissue; VEGF-A; VEGFR-1