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J. Biol. Chem., Vol. 279, Issue 18, 19230-19238, April 30, 2004

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Intercellular Adhesion Molecule-1 (ICAM-1) Regulates Endothelial Cell Motility through a Nitric Oxide-dependent Pathway^*

Christopher G. Kevil¶, A. Wayne Orr||, Will Langston, Kathryn Mickett||, Joanne Murphy-Ullrich||, Rakesh P. Patel||, Dennis F. Kucik||, and Daniel C. Bullard**

From the Departments of Pathology and Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130 and the Departments of ^||Molecular and Cellular Pathology, ^**Genomics and Pathobiology, and Medical Center and Department of Pathology Research Service, University of Alabama at Birmingham, Birmingham, Alabama 35294

Coordinated regulation of endothelial cell migration is an integral process during angiogenesis. However, molecular mechanisms regulating endothelial cell migration remain largely unknown. Increased expression of cell adhesion molecules has been implicated during angiogenesis, yet the precise role of these molecules is unclear. Here, we examined the hypothesis that intercellular adhesion molecule-1 (ICAM-1) is important for endothelial cell migration. Total cell displacement and directional migration were significantly attenuated in ICAM-1-deficient endothelium. Closer examination of ICAM-1-deficient cells revealed decreased Akt Thr³⁰⁸ and endothelial nitric-oxide synthase Ser¹¹⁷⁷ phosphorylation and NO bioavailability, increased actin stress fiber formation, and a lack of distinct cell polarity compared with wild-type endothelium. Supplementation of ICAM-1 mutant cells with the NO donor DETA NONOate (0.1 µM) corrected the migration defect, diminished stress fiber formation, and enhanced pseudopod and uropod formation. These data demonstrate that ICAM-1 facilitates the development of cell polarity and modulates endothelial cell migration through a pathway regulating endothelial nitric-oxide synthase activation and organization of the actin cytoskeleton.

Received for publication, November 3, 2003 , and in revised form, February 23, 2004.

^* This work was supported by National Institutes of Health Grant HL-010312 and an American Heart Association beginning grant-in-aid (to C. G. K.), by National Institutes of Health Grants HL-07918 (to A. W. O.), HL-70146 (to R. P. P.), HL-44575 (to J. M.-U.), and RR-17009 (to D. C. B.) and by a Veterans Affairs Medical Center merit review award (to D. F. K.). 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.

Both authors contributed equally to this work.

^¶ To whom correspondence should be addressed: Dept. of Pathology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130. Tel.: 318-675-4694; Fax: 318-675-7662; E-mail: ckevil{at}lsuhsc.edu.

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