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(Circulation. 2009;119:845-856.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Vascular Endothelial Growth Factor-B Induces Myocardium-Specific Angiogenesis and Arteriogenesis via Vascular Endothelial Growth Factor Receptor-1– and Neuropilin Receptor-1–Dependent Mechanisms

Johanna E. Lähteenvuo, MD; Markku T. Lähteenvuo, MD; Antti Kivelä, MD; Carolina Rosenlew, MSc; Annelie Falkevall, PhD; Joakim Klar, PhD; Tommi Heikura, MSc; Tuomas T. Rissanen, MD, PhD; Elisa Vähäkangas, MD; Petra Korpisalo, MD; Berndt Enholm, MD, PhD; Peter Carmeliet, MD, PhD; Kari Alitalo, MD, PhD; Ulf Eriksson, PhD; Seppo Ylä-Herttuala, MD, PhD, FESC

From the Department of Biotechnology and Molecular Medicine (J.E.L., M.T.L., A.K., T.H., T.T.R., E.V., P.K., S.Y.-H.), A.I. Virtanen Institute, University of Kuopio, Kuopio, Finland; Ludwig Institute for Cancer Research Ltd, Karolinska Institutet (C.R., A.F., J.K., U.E.), Stockholm, Sweden; Molecular and Cancer Biology Laboratory (B.E., K.A.), Haartman Institute, University of Helsinki, Helsinki, Finland; and Flanders Interuniversity Institute for Biotechnology (P.C.), Katholieke Universiteit Leuven, Leuven, Belgium.

Reprint requests to Seppo Ylä-Herttuala, MD, PhD, FESC, Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland. E-mail Seppo.Ylaherttuala{at}uku.fi

Received December 5, 2007; accepted December 9, 2008.

Background— New revascularization therapies are urgently needed for patients with severe coronary heart disease who lack conventional treatment options.

Methods and 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- interacting protein, terminus C (GIPC) and upregulation of G-protein- 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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2009 119: 765-767. [Extract] [Full Text]