Published online before print December 14, 2006, doi: 10.1161/01.RES.0000255685.06922.c7
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Submitted on July 25, 2005
Revised on November 10, 2006
Accepted on December 5, 2006
Human Vascular Smooth Muscle Cells Express Functionally Active Endothelial Cell Protein C Receptor
Ellen Bretschneider ;
From the Institut für Vaskuläre Medizin (E.B., B.U., K.L.), Klinikum der Friedrich-Schiller-Universität Jena; and Institut für Pharmakologie und Klinische Pharmakologie (A.-A.W., J.W.F., R.P., K.S.), Universitätsklinikum Düsseldorf, Germany. Current address for K.S.: Institut für Pharmakologie, Universitätsklinikum Essen, Germany.
* To whom correspondence should be addressed. E-mail: Karsten.Schroer{at}uni-duesseldorf.de.
The endothelial cell protein C receptor (EPCR) is expressed on endothelial cells and regulates the protein C anticoagulant pathway via the thrombin-thrombomodulin complex. Independent of its anticoagulant activity, activated protein C (APC) can directly signal to endothelial cells and upregulate antiapoptotic and antiinflammatory genes. Here we show that vascular smooth muscle cells (SMCs) also express EPCR. EPCR protein on SMCs was detected by flow cytometry and Western blotting. EPCR mRNA was identified by quantitative RT-PCR. To examine the functionality of EPCR, intracellular signaling in APC-stimulated SMCs was analyzed by determination of intracellular free calcium transients using confocal laser scanning microscopy. Phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK-1/2) was detected by immunoblotting. APC-induced ERK-1/2 phosphorylation was inhibited by an anti-EPCR antibody and by a cleavage site blocking anti-PAR-1 antibody, indicating that binding of APC to EPCR and cleavage of protease-activated receptor-1 (PAR-1) were involved. APC elicited an increase in [3H]-thymidine incorporation. The mitogenic effect of APC was significantly enhanced in the presence of thrombin. EPCR expression was also detected in SMCs in the fibrous cap of human carotid artery plaques. The present data demonstrate functionally active EPCR in SMCs and suggest that EPCR-bound APC might modulate PAR-1-mediated responses of SMCs to vascular injury.
Key words: endothelial cell protein C receptor • activated protein C • vascular smooth muscle cells • intracellular signaling
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