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J. Biol. Chem., Vol. 282, Issue 27, 19676-19684, July 6, 2007

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Osteopontin Overexpression Inhibits in Vitro Re-endothelialization via Integrin Engagement^*

Daria Leali, Emanuela Moroni, Federico Bussolino, and Marco Presta¹

From the Unit of General Pathology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, 25123 Brescia, Italy and the Institute for Cancer Research and Treatment, Department of Oncological Sciences, University of Torino, 10100 Turin, Italy

The extracellular matrix protein osteopontin (OPN) plays a nonredundant role in atherosclerosis and restenosis. Here we investigated the impact of OPN up-regulation in an in vitro model of re-endothelialization after mechanical injury of the endothelial cell monolayer. Murine aortic endothelial (MAE) cells interact via _v integrins with the integrin-binding Arg-Gly-Asp OPN sequence and adhere to immobilized OPN. On this basis, MAE cells were stably transfected with a wild-type OPN cDNA (OPN-MAE cells), with an OPN mutant lacking the Arg-Gly-Asp sequence (RGD-OPN-MAE cells), or with vector alone (mock-MAE cells). When compared with mock-MAE and RGD-OPN-MAE cells, OPN-MAE cells showed a reduced sprouting activity in fibrin gel, a reduced motility in a Boyden chamber assay, and a reduced capacity to repair the wounded monolayer. Accordingly, OPN-MAE cells at the edge of the wound were unable to form membrane ruffles, to reorganize their cytoskeleton, and to activate the focal adhesion kinase and the small GTPase Rac1, key regulators of the cell entry into the first phase of the cell migration cycle. Accordingly, wounded OPN-MAE cells failed to activate the intracellular signals RhoA and ERK1/2, involved in the later phases of the cell migration cycle. Also, parental MAE cells showed reduced re-endothelialization after wounding when seeded on immobilized OPN and exhibited increased adhesiveness to OPN-enriched extracellular matrix. In conclusion, OPN up-regulation impairs re-endothelialization by inhibiting the first phase of the cell migration cycle via _v integrin engagement by the extracellular matrix-immobilized protein. This may contribute to the adverse effects exerted by OPN in restenosis and atherosclerosis.

Received for publication, July 21, 2006 , and in revised form, March 22, 2007.

^* This study was supported by grants from Ministero dell'Istruzione, Università e Ricerca (Centro di Eccellenza per l'Innovazione Diagnostica e Terapeutica, Fondo per gli Investimenti della Ricerca di Base, and Cofin projects), Fondazione Berlucchi, and Istituto Superiore di Sanità (Progetto Oncotecnologico) (to M. P.); from Associazione Italiana per la Ricerca sul Cancro (to M. P. and F. B.); and from Regione Piemonte (to F. B.). 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 www.jbc.org) contains supplemental Figs. S1–S4.

¹ To whom correspondence should be addressed: General Pathology and Immunology, Dept. of Biomedical Sciences and Biotechnology, Viale Europa 11, 25123 Brescia, Italy. Tel.: 39-0303717311; Fax: 39-0303701157; E-mail: presta{at}med.unibs.it.

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