on June 22, 2006
Published online before print June 22, 2006, doi: 10.1161/01.ATV.0000233336.53574.a1
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Submitted on February 28, 2006
Accepted on April 30, 2006
Chimeric VEGF-ENZ7/PlGF Promotes Angiogenesis Via VEGFR-2 Without Significant Enhancement of Vascular Permeability and Inflammation
Yujuan Zheng ;
From the Division of Genetics, Institute of Medical Science (Y.Z., M.M., H.T., M.Y., A.K., S.Y., N.Y., M.S.), University of Tokyo, Japan; and the Molecular/Cancer Biology Laboratory (K.A.), Biomedicum Helsinki, and Ludwig Institute for Cancer Research, University of Helsinki, Finland.
* To whom correspondence should be addressed. E-mail: shibuya{at}ims.u-tokyo.ac.jp.
Objective--Vascular endothelial growth factor (VEGF) plays critical roles in the regulation of angiogenesis and lymphangiogenesis. However, tissue edema, hemorrhage, and inflammation occur when VEGF-A is used for angiogenic therapy. To design a novel angiogenic factor without severe side effects, we examined the biological function of chimeric VEGF-ENZ7/placental grown factor (PlGF), which is composed of Orf-VirusNZ7-derived VEGF-ENZ7 and human PlGF1, in a transgenic (Tg) mouse model.
Methods and Results--A strong angiogenic response was observed in both VEGF-ENZ7/PlGF and VEGF-A165 Tg mice. Notably, the vascular leakage of VEGF-ENZ7/PlGF-induced blood vessels was 4-fold lower than that of VEGF-A165-induced blood vessels. Furthermore, the monocyte/macrophage recruitment in the skin of VEGF-ENZ7/PlGF Tg mice was 
8-fold decreased compared with that of VEGF-A165 Tg mice. In addition, the lymphatic vessels in VEGF-ENZ7/PlGF Tg mice were structurally normal, whereas they were markedly dilated in VEGF-A165 Tg mice, possibly because of the high vascular leakage. Receptor binding assay demonstrated that VEGF-ENZ7/PlGF was the ligand only activating VEGF receptor (VEGFR)-2.
Conclusion--These results indicated that neither the hyperpermeability in response to simultaneous stimulation of VEGFR-1 and VEGFR-2 nor VEGFR-1-mediated severe inflammation was associated with VEGF-ENZ7/PlGF-induced angiogenesis. The unique receptor binding property may shed light on VEGF-ENZ7/PlGF as a novel candidate for therapeutic angiogenesis.
Key words: VEGF-ENZ7/PlGF • angiogenesis • VEGFR-2 • permeability • inflammation
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