title: Adventitial gene transfer of VEGFR-2 specific VEGF-E chimera induces MCP-1 expression in vascular smooth muscle cells and enhances neointimal formation.
abstract: BACKGROUND
  The role of vascular endothelial growth factors (VEGFs) in neointimal formation has been controversial. VEGF receptor (R)-2 signaling pathway is crucial in bringing about the effects of VEGFs including vasodilatation, endothelial cell migration and proliferation. In this study we have used an established adventitial gene transfer technique, in vitro studies and a novel VEGF-E/PlGF chimera that binds specifically to VEGFR-2, to investigate the role of VEGFR-2 in neointimal formation.
  
  
  METHODS
  Intimal hyperplasia was induced in the carotid arteries of cholesterol fed male New Zealand White rabbits using a silastic collar. Adenoviral vectors encoding VEGF-E chimera (1×10(9) pfu/ml) were transferred to the adventitia of the carotid arteries either alone or together with adenoviruses encoding soluble VEGFR-2 (sVEGFR-2). Adenoviruses encoding LacZ were used as controls. All animals were sacrificed 7 days after the gene transfer.
  
  
  RESULTS
  Significant increases in neointimal formation, proliferating cells, inflammatory responses and adventitial angiogenesis were observed in the VEGF-E chimera transduced arteries. The number of medial smooth muscle cells expressing VEGFR-2 was significantly (p<0.001) higher. MCP-1 mRNA levels were significantly (p<0.01) increased in the VEGF-E chimera transduced arteries and transduced rabbit aortic smooth muscle cells (p<0.05). Soluble VEGFR-2 (sVEGFR-2) significantly inhibited VEGF-E chimera induced neointimal formation (p<0.01), cellular proliferation (p<0.01), inflammatory responses (p<0.01) and adventitial angiogenesis (p<0.01).
  
  
  CONCLUSIONS
  The results indicate that VEGFR-2 mediated signaling could aggravate neointimal formation and suggest a potential therapeutic role of sVEGFR-2 in inhibiting neointimal formation and adventitial angiogenesis.
authors.affiliation: Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Shalini
authors.initials: S
authors.lastname: Bhardwaj
authors.forename: Himadri
authors.initials: H
authors.lastname: Roy
authors.forename: Mohan
authors.initials: M
authors.lastname: Babu
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Seppo
authors.initials: S
authors.lastname: Yla-Herttuala
mesh_terms: D000256:Adenoviridae / Q000502:physiology; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D018014:Gene Transfer Techniques; D006965:Hyperplasia / Q000473:pathology; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058426:Neointima / Q000139:chemically induced*; D009389:Neovascularization, Pathologic; D011817:Rabbits; D018183:Transplantation Chimera / Q000502:physiology; D017539:Tunica Intima / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; C084758:VEGF-like protein, Orf virus; D014764:Viral Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2