title: Vascular endothelial growth factor-B induces myocardium-specific angiogenesis and arteriogenesis via vascular endothelial growth factor receptor-1- and neuropilin receptor-1-dependent mechanisms.
abstract: BACKGROUND
  New revascularization therapies are urgently needed for patients with severe coronary heart disease who lack conventional treatment options.
  
  
  RESULTS
  We describe a new proangiogenic approach for these no-option patients using adenoviral (Ad) intramyocardial vascular endothelial growth factor (VEGF)-B186 gene transfer, which induces myocardium-specific angiogenesis and arteriogenesis in pigs and rabbits. After acute infarction, AdVEGF-B186 increased blood vessel area, perfusion, ejection fraction, and collateral artery formation and induced changes toward an ischemia-resistant myocardial phenotype. Soluble VEGF receptor-1 and soluble neuropilin receptor-1 reduced the effects of AdVEGF-B186, whereas neither soluble VEGF receptor-2 nor inhibition of nitric oxide production had this result. The effects of AdVEGF-B186 involved activation of neuropilin receptor-1, which is highly expressed in the myocardium, via recruitment of G-protein-alpha interacting protein, terminus C (GIPC) and upregulation of G-protein-alpha interacting protein. AdVEGF-B186 also induced an antiapoptotic gene expression profile in cardiomyocytes and had metabolic effects by inducing expression of fatty acid transport protein-4 and lipid and glycogen accumulation in the myocardium.
  
  
  CONCLUSIONS
  VEGF-B186 displayed strikingly distinct effects compared with other VEGFs. These effects may be mediated at least in part via a G-protein signaling pathway. Tissue-specificity, high efficiency in ischemic myocardium, and induction of arteriogenesis and antiapoptotic and metabolic effects make AdVEGF-B186 a promising candidate for the treatment of myocardial ischemia.
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, Kuopio, Finland.
authors.forename: Johanna E
authors.initials: JE
authors.lastname: Lähteenvuo
authors.forename: Markku T
authors.initials: MT
authors.lastname: Lähteenvuo
authors.forename: Antti
authors.initials: A
authors.lastname: Kivelä
authors.forename: Carolina
authors.initials: C
authors.lastname: Rosenlew
authors.forename: Annelie
authors.initials: A
authors.lastname: Falkevall
authors.forename: Joakim
authors.initials: J
authors.lastname: Klar
authors.forename: Tommi
authors.initials: T
authors.lastname: Heikura
authors.forename: Tuomas T
authors.initials: TT
authors.lastname: Rissanen
authors.forename: Elisa
authors.initials: E
authors.lastname: Vähäkangas
authors.forename: Petra
authors.initials: P
authors.lastname: Korpisalo
authors.forename: Berndt
authors.initials: B
authors.lastname: Enholm
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Ulf
authors.initials: U
authors.lastname: Eriksson
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000254:growth & development; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D009203:Myocardial Infarction / Q000628:therapy; D017202:Myocardial Ischemia / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D039942:Neuropilin-1 / Q000378:metabolism*; D009928:Organ Specificity; D011817:Rabbits; D013552:Swine; D042561:Vascular Endothelial Growth Factor B / Q000008:administration & dosage*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D042561:Vascular Endothelial Growth Factor B; D039942:Neuropilin-1; D040281:Vascular Endothelial Growth Factor Receptor-1