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J. Biol. Chem., Vol. 280, Issue 23, 22445-22453, June 10, 2005

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Effects of Protein and Gene Transfer of the Angiopoietin-1 Fibrinogen-like Receptor-binding Domain on Endothelial and Vessel Organization^*

Cornelia C. Weber, Hao Cai, Martin Ehrbar, Hisashi Kubota¶, Georg Martiny-Baron||, Wilfried Weber**, Valentin Djonov, Ernst Weber, Ajit S. Mallik, Martin Fussenegger**, Karl Frei¶, Jeffrey A. Hubbell¶¶, and Andreas H. Zisch||||

From the Department of Materials Science and the Institute of Biomedical Engineering, Swiss Federal Institute of Technology Zurich and University of Zurich, Zurich 8044, Switzerland, the Departments of ^¶Neurosurgery and Obstetrics, University Hospital Zurich, Zurich 8091, Switzerland, ^||Novartis Pharma AG, Basel 4002, Switzerland, the ^**Institute of Biotechnology, Swiss Federal Institute of Technology Zurich, Zurich 8093, Switzerland, the Institute of Anatomy, University of Berne, Berne 3000, Switzerland, and the Department of Biostatistics, German Cancer Research Center, Heidelberg 69 210, Germany

The vessel-stabilizing effect of angiopoietin-1 (Ang1)/Tie2 receptor signaling is a potential target for pro-angiogenic therapies as well as anti-angiogenic inhibition of tumor growth. We explored the endothelial and vascular specific activities of the Ang1 monomer, i.e. dissociated from its state as an oligomer. A truncated monomeric Ang1 variant (i.e. Ang1) containing the isolated fibrinogen-like receptor-binding domain of Ang1 was created and recombinantly produced in insect cells. Ang1 ligated the Tie2 receptor without triggering its phosphorylation. Moreover, monomeric Ang1 was observed to bind ₅₁ integrin with similar affinity compared with Tie2. Unexpectedly, in vitro treatment of endothelial cells with Ang1 showed some of the known effects of full-length Ang1, including inhibition of basal endothelial cell permeability and stimulation of cell adhesion as well as activation of MAPKs. Local treatment of the microvasculature of the developing chicken chorioallantoic membrane with the Ang1 protein led to profound reduction of the mean vascular length density, thinning of vessels, and reduction of the number of vessel branching points. Similar effects were observed in side-by-side experiments with the recombinant full-length Ang1 protein. These effects of simplification of the vessel branching pattern were confirmed through local gene transfer with lentiviral particles encoding Ang1 or full-length Ang1. Together, our findings suggest a potential use for exogenous Ang1 in reducing rather than increasing vascular density. Furthermore, we show that the isolated receptor-binding domain of Ang1 is capable of mediating some effects of full-length Ang1 independently of Tie2 phosphorylation, possibly through integrin ligation.

Received for publication, September 9, 2004 , and in revised form, February 22, 2005.

^* This work was supported by Grant TH 00816 from the Swiss Federal Institute of Technology Zurich and Grant P-1041 from the Gebert Rüf Foundation (to A. H. Z. and J. A. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Tables 1 and 2 and a supplemental figure.

^¶¶ Present address: Lab. for Regenerative Medicine and Pharmacobiology, Integrative Biosciences Inst., Ecole Polytechnique Fédérale de Lausanne, Lausanne 1050, Switzerland.

^|||| To whom correspondence should be addressed: Dept. of Obstetrics, University Hospital Zurich, Frauenklinikstra. 10, Zurich 8091, Switzerland. Tel.: 41-1-255-5149; Fax: 41-1-255-4430; E-mail: andreas.zisch{at}usz.ch.

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