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J. Biol. Chem., Vol. 280, Issue 2, 1292-1298, January 14, 2005

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Membrane Type 1-Matrix Metalloproteinase Is Regulated by Chemokines Monocyte-Chemoattractant Protein-1/CCL2 and Interleukin-8/CXCL8 in Endothelial Cells during Angiogenesis^*

Beatriz G. Gálvez, Laura Genís, Salomón Matías-Román, Samantha A. Oblander¶, Karl Tryggvason||, Suneel S. Apte¶, and Alicia G. Arroyo**

From the Departamento de Investigación Básica, Centro Nacional de Investigaciones Cardiovasculares, Ronda de Poniente, 5, 28760-Tres Cantos, Spain, ^¶Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, and ^||Department of Matrix Biology and Biochemistry, Karolinska Institute, S-171 77 Stockholm, Sweden

We have investigated the putative role and regulation of membrane type 1-matrix metalloproteinase (MT1-MMP) in angiogenesis induced by inflammatory factors of the chemokine family. The absence of MT1-MMP from null mice or derived mouse lung endothelial cells or the blockade of its activity with inhibitory antibodies resulted in the specific decrease of in vivo and in vitro angiogenesis induced by CCL2 but not CXCL12. Similarly, CCL2- and CXCL8-induced tube formation by human endothelial cells (ECs) was highly dependent on MT1-MMP activity. CCL2 and CXCL8 significantly increased MT1-MMP surface expression, clustering, activity, and function in human ECs. Investigation of the signaling pathways involved in chemokine-induced MT1-MMP activity in ECs revealed that CCL2 and CXCL8 induced cortical actin polymerization and sustained activation of phosphatidylinositol 3-kinase (PI3K) and the small GTPase Rac. Inhibition of PI3K or actin polymerization impaired CCL2-induced MT1-MMP activity. Finally, dimerization of MT1-MMP was found to be enhanced by CCL2 in ECs in a PI3K- and actin polymerization-dependent manner. In summary, we identify MT1-MMP as a molecular target preferentially involved in angiogenesis mediated by CCL2 and CXCL8, but not CXCL12, and suggest that MT1-MMP dimerization might be an important mechanism of its regulation during angiogenesis.

Received for publication, July 30, 2004 , and in revised form, October 14, 2004.

^* This work was supported by National Institutes of Health Grant AR47074 (to S. A.) and by Comunidad Autónoma de Madrid Grant CAM 08.3/0015.1/2001, Spanish Ministerio de Ciencia y Tecnología Grant SAF2002-00068, Fundación ICO and by Biogen Inc. (to A. G. A.). 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.

A predoctoral fellow from the Comunidad Autónoma de Madrid.

^** To whom correspondence should be addressed. Tel.: 34-91-8061880 (ext. 1131); Fax: 34-91-8035258; E-mail: agarroyo{at}cnic.es.

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