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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2019.)
© 2006 American Heart Association, Inc.

Vascular Biology

Chimeric VEGF-E_NZ7/PlGF Promotes Angiogenesis Via VEGFR-2 Without Significant Enhancement of Vascular Permeability and Inflammation

Yujuan Zheng; Masato Murakami; Hiroyuki Takahashi; Mai Yamauchi; Atsushi Kiba; Sachiko Yamaguchi; Naoyuki Yabana; Kari Alitalo; Masabumi Shibuya

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.

Correspondence to Dr Masabumi Shibuya, Division of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan. 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-E_NZ7/placental growth factor (PlGF), which is composed of Orf-Virus_NZ7-derived VEGF-E_NZ7 and human PlGF1, in a transgenic (Tg) mouse model.

Methods and Results— A strong angiogenic response was observed in both VEGF-E_NZ7/PlGF and VEGF-A₁₆₅ Tg mice. Notably, the vascular leakage of VEGF-E_NZ7/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-E_NZ7/PlGF Tg mice was &8-fold decreased compared with that of VEGF-A₁₆₅ Tg mice. In addition, the lymphatic vessels in VEGF-E_NZ7/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-E_NZ7/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-E_NZ7/PlGF-induced angiogenesis. The unique receptor binding property may shed light on VEGF-E_NZ7/PlGF as a novel candidate for therapeutic angiogenesis.

We report here that chimeric VEGF-E_NZ7/PlGF composed of Orf-Virus_NZ7–derived VEGF-E_NZ7 and human PlGF1 induces strong angiogenic response, less monocyte/macrophage recruitment, and low vascular leakage in vivo because of its VEGFR-2 specificity. The unique receptor binding property may shed light on VEGF-E_NZ7/PlGF as a novel candidate molecule for therapeutic angiogenesis.

Key Words: VEGF-E_NZ7/PlGF • angiogenesis • VEGFR-2 • permeability • inflammation

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