Enhanced capillary formation stimulated by a chimeric vascular endothelial growth factor/vascular endothelial growth factor-C silk domain fusion protein.
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.
Keskitalo
Salla
S
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
Tammela
Tuomas
T
Lyytikka
Johannes
J
Karpanen
Terhi
T
Jeltsch
Michael
M
Markkanen
Johanna
J
Yla-Herttuala
Seppo
S
Alitalo
Kari
K
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001485:Basement Membrane / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D042601:Lymphatic Vessels / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D020286:Pericytes / Q000187:drug effects; D017434:Protein Structure, Tertiary; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology*; D042582:Vascular Endothelial Growth Factor C / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D040262:Receptors, Vascular Endothelial Growth Factor