Vascular endothelial growth factor-B induces myocardium-specific angiogenesis and arteriogenesis via vascular endothelial growth factor receptor-1- and neuropilin receptor-1-dependent mechanisms.
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.
Lähteenvuo
Johanna E
JE
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, Kuopio, Finland.
Lähteenvuo
Markku T
MT
Kivelä
Antti
A
Rosenlew
Carolina
C
Falkevall
Annelie
A
Klar
Joakim
J
Heikura
Tommi
T
Rissanen
Tuomas T
TT
Vähäkangas
Elisa
E
Korpisalo
Petra
P
Enholm
Berndt
B
Carmeliet
Peter
P
Alitalo
Kari
K
Eriksson
Ulf
U
Ylä-Herttuala
Seppo
S
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*
D042561:Vascular Endothelial Growth Factor B; D039942:Neuropilin-1; D040281:Vascular Endothelial Growth Factor Receptor-1