title: Chimeric VEGF-E(NZ7)/PlGF promotes angiogenesis via VEGFR-2 without significant enhancement of vascular permeability and inflammation.
abstract: OBJECTIVE
  Vascular endothelial growth factor (VEGF) plays critical roles in the regulation of angiogenesis and lymphangiogenesis. However, tissue edema, hemorrhage, and inflammation occur when VEGF-A is used for angiogenic therapy. To design a novel angiogenic factor without severe side effects, we examined the biological function of chimeric VEGF-E(NZ7)/placental growth factor (PlGF), which is composed of Orf-Virus(NZ7)-derived VEGF-E(NZ7) and human PlGF1, in a transgenic (Tg) mouse model.
  
  
  RESULTS
  A strong angiogenic response was observed in both VEGF-E(NZ7)/PlGF and VEGF-A165 Tg mice. Notably, the vascular leakage of VEGF-E(NZ7)/PlGF-induced blood vessels was 4-fold lower than that of VEGF-A165-induced blood vessels. Furthermore, the monocyte/macrophage recruitment in the skin of VEGF-E(NZ7)/PlGF Tg mice was approximately 8-fold decreased compared with that of VEGF-A165 Tg mice. In addition, the lymphatic vessels in VEGF-E(NZ7)/PlGF Tg mice were structurally normal, whereas they were markedly dilated in VEGF-A165 Tg mice, possibly because of the high vascular leakage. Receptor binding assay demonstrated that VEGF-E(NZ7)/PlGF was the ligand only activating VEGF receptor (VEGFR)-2.
  
  
  CONCLUSIONS
  These results indicated that neither the hyperpermeability in response to simultaneous stimulation of VEGFR-1 and VEGFR-2 nor VEGFR-1-mediated severe inflammation was associated with VEGF-E(NZ7)/PlGF-induced angiogenesis. The unique receptor binding property may shed light on VEGF-E(NZ7)/PlGF as a novel candidate for therapeutic angiogenesis.
authors.affiliation: Division of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Masato
authors.initials: M
authors.lastname: Murakami
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kiba
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Yabana
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced*; D042583:Lymphangiogenesis / Q000187:drug effects; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D039942:Neuropilin-1 / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics; D020286:Pericytes / Q000166:cytology; D011506:Proteins / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C098069:PIGF protein, human; D010446:Peptide Fragments; D011506:Proteins; D011993:Recombinant Fusion Proteins; C084758:VEGF-like protein, Orf virus; D042461:Vascular Endothelial Growth Factor A; D014764:Viral Proteins; C511613:vascular endothelial growth factor A (138-165); D039942:Neuropilin-1; D040301:Vascular Endothelial Growth Factor Receptor-2