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J. Biol. Chem., Vol. 282, Issue 21, 15679-15689, May 25, 2007

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The Contributions of Integrin Affinity and Integrin-Cytoskeletal Engagement in Endothelial and Smooth Muscle Cell Adhesion to Vitronectin^*

Steingrimur Stefansson¹, Enming J. Su, Shoji Ishigami, Jacqueline M. Cale, Yamei Gao, Natalia Gorlatova^¶, and Daniel A. Lawrence

From the Department of Physiology and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201, the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, and the ^¶University of Maryland Biotechnology Institute Center for Advanced Research in Biotechnology, Rockville, Maryland 20850

The serine proteinase inhibitor, plasminogen activator inhibitor type-1 (PAI-1), binds to the adhesion protein vitronectin with high affinity at a site that is located directly adjacent to the vitronectin RGD integrin binding sequence. The binding of PAI-1 to vitronectin sterically blocks integrin access to this site and completely inhibits the binding of purified integrins to vitronectin; however, its inhibition of endothelial and smooth muscle cell adhesion to vitronectin is at most 50-75%. Because PAI-1 binds vitronectin with 10-100-fold higher affinity than purified integrins, we have analyzed the mechanism whereby these cells are able to overcome this obstacle. Our studies exclude proteolytic removal of PAI-1 from vitronectin as the mechanism, and show instead that cell adhesion in the presence of PAI-1 is dependent on integrin-cytoskeleton engagement. Disrupting endothelial or smooth muscle cell actin polymerization and/or focal adhesion assembly reduces cell adhesion to vitronectin in the presence of PAI-1 to levels similar to that observed for the binding of purified integrins to vitronectin. Furthermore, endothelial cell, but not smooth muscle cell adhesion to vitronectin in the presence of PAI-1 requires both polymerized microtubules and actin, further demonstrating the importance of the cytoskeleton for integrin-mediated adhesion. Finally, we show that cell adhesion in the presence of PAI-1 leads to colocalization of PAI-1 with the integrins v3 and v5 at the cell-matrix interface.

Received for publication, March 12, 2007

^* This work was supported in part by National Institutes of Health Grants HL055747, HL055374, HL054710, and HL069624. 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.

¹ To whom correspondence should be addressed: Creatv MicroTech, 11609 Lake Potomac Dr., Potomac, MD 20854. E-mail: stenni{at}creatvmicrotech.com.

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