Published online before print May 3, 2007, doi: 10.1161/01.RES.0000269042.58594.f6
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on December 21, 2006
Revised on March 30, 2007
Accepted on April 25, 2007
Enhanced Capillary Formation Stimulated by a Chimeric Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor-C Silk Domain Fusion Protein
Salla Keskitalo ;
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.
* To whom correspondence should be addressed. 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
This article has been cited by other articles:
 |
|
 |
|
  A. Anisimov, A. Alitalo, P. Korpisalo, J. Soronen, S. Kaijalainen, V.-M. Leppanen, M. Jeltsch, S. Yla-Herttuala, and K. Alitalo Activated Forms of VEGF-C and VEGF-D Provide Improved Vascular Function in Skeletal Muscle Circ. Res., June 5, 2009; 104(11): 1302 - 1312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Simons Silky, Sticky Chimeras-Designer VEGFs Display Their Wares Circ. Res., May 25, 2007; 100(10): 1402 - 1404. [Full Text] [PDF]
|
|