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J. Biol. Chem., Vol. 280, Issue 23, 22308-22317, June 10, 2005

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Caveolin-1 Enhances Tissue Factor Pathway Inhibitor Exposure and Function on the Cell Surface^*

Cristina Lupu, Xiaohong Hu, and Florea Lupu¶

From the Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, and the ^¶Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104

Tissue factor pathway inhibitor (TFPI) blocks tissue factor-factor VIIa (TF-FVIIa) activation of factors X and IX through the formation of the TF-FVIIa-FXa-TFPI complex. Most TFPI in vivo associates with caveolae in endothelial cells (EC). The mechanism of this association and the anticoagulant role of caveolar TFPI are not yet known. Here we show that expression of caveolin-1 (Cav-1) in 293 cells keeps TFPI exposed on the plasmalemma surface, decreases the membrane lateral mobility of TFPI, and increases the TFPI-dependent inhibition of TF-FVIIa. Caveolae-associated TFPI supports the co-localization of the quaternary complex with caveolae. To investigate the significance of these observations for EC we used RNA interference to deplete the cells of Cav-1. Functional assays and fluorescence microscopy revealed that the inhibitory properties of TFPI were diminished in EC lacking Cav-1, apparently through deficient assembly of the quaternary complex. These findings demonstrate that caveolae regulate the inhibition by cell-bound TFPI of the active protease production by the extrinsic pathway of coagulation.

Received for publication, March 25, 2005

^* This work was supported by American Heart Association Beginning Grant-in-aid 0265213Z and National Institutes of Health COBRE Program Grant 5P20RR018758-02. 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 http://www.jbc.org) contains data and Figs. S1—S5.

To whom correspondence should be addressed: Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104. Tel.: 405-271-7206; Fax: 405-271-7417; E-mail: cristina-lupu{at}omrf.ouhsc.edu.

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