title: Vascular endothelial growth factor C-induced collateral formation in a model of myocardial ischemia.
abstract: BACKGROUND
  Besides being a known lymphangiogenic activator, vascular endothelial growth factor (VEGF)-C may express angiogenic potential by proteolytic cleavage and activation of endothelial cells. We assessed myocardial collateral formation and functional changes after adenovirus-mediated VEGF-C gene transfer in an ischemic porcine model.
  
  
  METHODS
  Fifteen Landrace piglets underwent Ameroid-induced gradual occlusion of the left circumflex artery (LCx) and consequent progressive myocardial ischemia. Three weeks after Ameroid placement, the animals underwent gated 99mTc SPECT during rest and stress, in vivo angiography and 18FDG PET. Pigs were randomized to intramyocardial injections of adenoviruses encoding vascular endothelial growth factor (VEGF-C; n = 7) or control beta-galactosidase (LacZ; n = 5). Four weeks later, the examinations were repeated and histology was analyzed.
  
  
  RESULTS
  Angiography showed significant progression of LCx stenosis in both groups during the treatment period. Left ventricular wall thickening (LVWT) at the LCx area in gated 99mTc SPECT remained unchanged in the VEGF-C group, indicating that VEGF-C prevented progression of myocardial ischemia, whereas LVWT deteriorated in the LacZ group (p = 0.042). Semi-quantitative assessment of 18FDG PET suggests more reduction in ischemia in the adVEGF-C group than in controls (p = 0.052). Angiography showed significant clustering of collaterals in the adVEGF-C gene transfer area compared that in LacZ (p = 0.004). von Willebrand factor staining revealed a significantly (p = 0.03) greater number of microvessels in the adVEGF-C-treated myocardium.
  
  
  CONCLUSIONS
  This appears to be the first large-animal study in which, during progressive ischemia, functional and metabolic benefits of intramyocardial VEGF-C gene transfer were apparent. VEGF-C-induced collateral formation occurred at the site of gene transfer. The angiogenic potency of VEGF-C deserves further study as a therapeutic option.
authors.affiliation: Department of Cardiothoracic Surgery, University of Helsinki, Meilahti Hospital, Helsinki, Finland. tommi.patila@hus.fi
authors.forename: Tommi
authors.initials: T
authors.lastname: Pätilä
authors.forename: Tuija
authors.initials: T
authors.lastname: Ikonen
authors.forename: Juha
authors.initials: J
authors.lastname: Rutanen
authors.forename: Aapo
authors.initials: A
authors.lastname: Ahonen
authors.forename: Jyri
authors.initials: J
authors.lastname: Lommi
authors.forename: Kimmo
authors.initials: K
authors.lastname: Lappalainen
authors.forename: Leena
authors.initials: L
authors.lastname: Krogerus
authors.forename: Leo
authors.initials: L
authors.lastname: Ihlberg
authors.forename: Taina A
authors.initials: TA
authors.lastname: Partanen
authors.forename: Liisa
authors.initials: L
authors.lastname: Lähteenoja
authors.forename: Kari
authors.initials: K
authors.lastname: Virtanen
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Ari
authors.initials: A
authors.lastname: Harjula
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003097:Collateral Circulation / Q000502:physiology*; D017023:Coronary Angiography; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D008833:Microcirculation / Q000473:pathology / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D018919:Neovascularization, Physiologic / Q000235:genetics*; D049268:Positron-Emission Tomography; D011897:Random Allocation; D013552:Swine; D015899:Tomography, Emission-Computed, Single-Photon; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics* / Q000502:physiology*
chemical_list: D042582:Vascular Endothelial Growth Factor C