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J. Biol. Chem., Vol. 279, Issue 53, 55905-55913, December 31, 2004

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Endothelial Cell Confluence Regulates Cyclooxygenase-2 and Prostaglandin E₂ Production That Modulate Motility^*

Huimiao Jiang, Andrew S. Weyrich¶, Guy A. Zimmerman¶, and Thomas M. McIntyre¶||

From the Departments of Pathology, Human Molecular Biology and Genetics, and ^¶Medicine, University of Utah, Salt Lake City, Utah 84112-5330

Endothelial cells line the vasculature and, after mechanical denudation during invasive procedures or cellular loss from natural causes, migrate to reestablish a confluent monolayer. We find confluent monolayers of human umbilical vein endothelial cells were quiescent and expressed low levels of cyclooxygenase-2, but expressed cyclooxygenase-2 at levels comparable with cytokine-stimulated cells when present in a subconfluent culture. Mechanically wounding endothelial cell monolayers stimulated rapid cyclooxygenase-2 expression that increased with the level of wounding. Cyclooxygenase-2 re-expression occurred throughout the culture, suggesting signaling from cells proximal to the wound to distal cells. Media from wounded monolayers stimulated cyclooxygenase-2 expression in confluent monolayers, which correlated with the level of wounding of the donor monolayer. Wounded monolayers and cells in subconfluent cultures secreted enhanced levels of prostaglandin (PG) E₂ that depended on cyclooxygenase-2 activity, and PGE₂ stimulated cyclooxygenase-2 expression in confluent endothelial cell monolayers. Cells from subconfluent monolayers migrated through filters more readily than those from confluent monolayers, and the cyclooxygenase-2-selective inhibitor NS-398 suppressed migration. Adding PGE₂ to NS-398-treated cells augmented migration. Endothelial cells also migrated into mechanically denuded areas of confluent monolayers, and this too was suppressed by NS-398. We conclude that endothelial cells not in contact with neighboring cells express cyclooxygenase-2 that results in enhanced release of PGE₂, and that this autocrine and paracrine loop enhances endothelial cell migration to cover denuded areas of the endothelium.

Received for publication, June 2, 2004 , and in revised form, September 7, 2004.

^* This work was supported in part by National Institutes of Health Grants HL44513 and HL44525. 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.

^|| To whom correspondence should be addressed: Dept. of Cell Biology, NC-10, Cleveland Clinic Foundation, Cleveland, OH 44195. Tel.: 216-444-1048; Fax: 216-444-9404; E-mail: mcintyt{at}ccf.org.

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