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 Blood, 15 May 2004, Vol. 103, No. 10, pp. 3760-3765.
Prepublished online as a Blood First Edition Paper on February 5, 2004; DOI 10.1182/blood-2003-04-1272.

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Submitted April 23, 2003
Accepted December 19, 2003

Angiopoietin-related growth factor (AGF) promotes angiogenesis

Yuichi Oike*, Yasuhiro Ito, Hiromitsu Maekawa, Tohru Morisada, Yoshiaki Kubota, Masaki Akao, Takashi Urano, Kunio Yasunaga, and Toshio Suda

Department of Cell Differentiation, Keio University, School of Medicine, Tokyo, Japan
Molecular Medicine Laboratories, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba, Japan

* Corresponding author; email: oike{at}sc.itc.keio.ac.jp.

We report here the identification of angiopoietin-related growth factor (AGF) as a positive mediator for angiogenesis. To investigate the biological function of AGF in angiogenesis, we analyzed the vasculature in the dermis of transgenic mice expressing AGF in mouse epidermal keratinocytes (K14-AGF). K14-AGF transgenic mice were grossly red, especially in ears and snout, suggesting that hypervascularization had occurred in their skin. Histological examination of ear skin from K14-AGF transgenic mice revealed increased numbers of microvessels in the dermis, whereas the expression of several angiogenic factors such as bFGF, VEGFs and angiopoietin1 was decreased. We showed that AGF is a secreted protein and does not bind to Tie1 or Tie2 receptors. An in vitro chamber assay revealed that AGF directly promotes chemotactic activity of vascular endothelial cells. Both mouse corneal and matrigel plug assays showed that AGF induces neovascularization in vivo. Furthermore, we found that plasma leakage occurred after direct injection of AGF into the mouse dermis, suggesting that AGF directly induces a permeability change in the local vasculature. On the basis of these observations, we propose that AGF is a novel angiogenic factor and that handling of its biological functions could lead to novel therapeutic strategies for control of angiogenesis.


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