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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:503.)
© 2007 American Heart Association, Inc.

Vascular Biology

Chimeric VEGF-E_NZ7/PlGF Specifically Binding to VEGFR-2 Accelerates Skin Wound Healing via Enhancement of Neovascularization

Yujuan Zheng; Makoto Watanabe; Takeshi Kuraishi; Shosaku Hattori; Chieko Kai; Masabumi Shibuya

From the Division of Genetics (Y.Z., M.W., M.S.), Laboratory Animal Research Center and Amami Laboratory of Injurious Animals (T.K., S.H., C.K.), Institute of Medical Science, University of Tokyo, Japan.

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— VEGF-E_NZ7/PlGF molecules composed of Orf virus-derived VEGF-E_NZ7 and human PlGF1 were previously proven to be potent angiogenic factors stimulating angiogenesis without significant enhancement of vascular leakage and inflammation in vivo. For its future clinical application, there is a pressing need to better understand the beneficial effects of VEGF-E_NZ7/PlGF during wound healing in adulthood.

Methods and Results— In this study, several angiogenic factors were administrated to skin punched wounds of both wild-type and diabetic mice. The treatment with VEGF-E_NZ7/PlGF accelerated wound closure accompanied with enhanced angiogenesis, the process was occurring slightly faster than that in VEGF-A₁₆₄ group. Moreover, the macrophage infiltration and lymphangiogenesis level in healed wounds were strikingly lower in VEGF-E_NZ7/PlGF group than VEGF-A₁₆₄ group, suggesting that the increased inflammation was the key issue preventing speedy wound healing of VEGF-A₁₆₄–treated skin. Considering clinical safety, we further examined the antigenicity of chimeric VEGF-E_NZ7/PlGF. Compared with the original VEGF-E_NZ7, the immunogenicity of VEGF-E_NZ7/PlGF molecules was markedly decreased in mice and squirrel monkeys with the increase of PlGF1 humanized ratio.

Conclusion— These results indicate that VEGF-E_NZ7/PlGF molecules are superior to VEGF-A for the acceleration of either normal or delayed skin wound healing and might be regarded as potential drugs in therapeutic angiogenesis.

We report here that chimeric VEGF-E_NZ7/PlGF molecules of low antigenicity accelerate skin wound healing with enhanced angiogenesis, less macrophage infiltration and lymphangiogenesis in both wild-type and diabetic mouse model. These findings clearly indicate that chimeric VEGF-E_NZ7/PlGF molecules are superior to VEGF-A, and might be the potential drugs in therapeutic angiogenesis.

Key Words: VEGF-E_NZ7/PlGF • wound healing • angiogenesis • lymphangiogenesis • inflammation

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