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

Circ Res. 2007 May 25;100(10):1460-7. doi: 10.1161/01.RES.0000269042.58594.f6. Epub 2007 May 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Basement Membrane / drug effects
  • Capillaries / drug effects
  • Capillaries / physiology
  • Cells, Cultured
  • Humans
  • Lymphatic Vessels / drug effects
  • Lymphatic Vessels / physiology
  • Mice
  • Neovascularization, Physiologic / drug effects*
  • Pericytes / drug effects
  • Protein Structure, Tertiary
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Recombinant Fusion Proteins / pharmacology*
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor A / pharmacology*
  • Vascular Endothelial Growth Factor C / chemistry
  • Vascular Endothelial Growth Factor C / metabolism
  • Vascular Endothelial Growth Factor C / pharmacology*

Substances

  • Recombinant Fusion Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • Receptors, Vascular Endothelial Growth Factor