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(Circulation Research. 2007;100:1460.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Enhanced Capillary Formation Stimulated by a Chimeric Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor-C Silk Domain Fusion Protein

Salla Keskitalo^*, Tuomas Tammela^*, Johannes Lyytikka, Terhi Karpanen, Michael Jeltsch, Johanna Markkanen, Seppo Yla-Herttuala, Kari Alitalo

From the Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research (S.K., T.T., J.L., T.K., M.J., K.A.), Biomedicum Helsinki, Haartman Institute and Helsinki University Central Hospital, University of Helsinki; and The A.I. Virtanen Institute and Department of Medicine (J.M., S.Y.-H.), University of Kuopio, Finland.

Correspondence to Dr Kari Alitalo, University of Helsinki, Molecular/Cancer Biology Program, Biomedicum Helsinki, POB 23 (Haartmaninkatu 8), Helsinki 00014, Finland. E-mail Kari.Alitalo{at}helsinki.fi

Vascular endothelial growth factor (VEGF)-C and VEGF-D require proteolytic cleavage of the carboxy terminal silk-homology domain for activation. To study the functions of the VEGF-C propeptides, we engineered a chimeric growth factor protein, VEGF-CAC, composed of the amino- and carboxy-terminal propeptides of VEGF-C fused to the receptor-activating core domain of VEGF. Like VEGF-C, VEGF-CAC underwent proteolytic cleavage, and like VEGF, it bound to and activated VEGF receptor-1 and VEGF receptor-2, but not the VEGF-C receptor VEGF receptor-3. VEGF-CAC also bound to neuropilins in a heparin-dependent manner. Strikingly, when VEGF-CAC was expressed via an adenovirus vector in the ear skin of immunodeficient mice, it proved to be a more potent inducer of capillary angiogenesis than VEGF. The VEGF-CAC–induced vessels differed greatly from those induced by VEGF, as they formed a very dense and fine network of pericyte and basement membrane–covered capillaries that were functional, as shown by lectin perfusion experiments. VEGF-CAC could prove useful in proangiogenic therapies in patients experiencing tissue ischemia.

Key Words: proangiogenic therapy • gene therapy • growth factors

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