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(Circulation Research. 2007;100:e86.)
© 2007 American Heart Association, Inc.

Letters to the Editor

The Endothelial Protein C Receptor in Vascular Smooth Muscle Cells For Good or Bad?

Shi-Sheng Li, Lihua Wu, José A. Fernández

Department of Molecular and Experimental Medicine, Department of Immunology, The Scripps Research Institute, La Jolla, California

An extract of the first 250 words of the full text is provided, because this article has no abstract.

To the Editor:

We read with great interest the recent article by Bretschneider et al,¹ who studied the protease activated receptor (PAR)-1-dependent protein C signaling in vascular smooth muscle cells (VSMCs). These data add another piece of evidence to the emerging concept that the endothelial protein C receptor (EPCR) exerts pleiotropic cellular effects.

Previous studies from several laboratories have concluded that EPCR ligation with activated protein C (APC) can lead to the proteolytic cleavage of PAR-1 on the surface of endothelial cells (ECs), leading to pleiotropic cellular effects, decreasing inflammation and apoptosis, and enhancing endothelium barrier protection.^2–7 Bretschneider et al¹ found that simultaneous stimulation of VSMCs with thrombin and the PAR-1 activating peptide (AP) does not result in a synergistic effect on cellular proliferation whereas the combination of APC treatment with thrombin or PAR-1 AP promotes additional proliferation; these data are in agreement with earlier observations by Uchiba et al⁸ in which APC treatment activates mitogen activated protein kinase pathway (MAPK) signaling in endothelial cells. Uchiba et al⁸ also observed that an anti-PAR-1 blocking antibody only partially inhibits the MAPK signals initiated by APC whereas the same antibody completely inhibits thrombin-induced MAPK activation.

Two important questions arise from these observations. First, does the EPCR-APC complex initiate PAR-1-independent signaling pathway in VSMCs? EPCR does not possess intrinsic catalytic activity, thus, PAR-1-independent signaling events would be mediated by either the association of EPCR with other receptor or the clustering of signaling proteins with EPCR cytoplasmic domain. Because of the fact that EPCR . . . [Full Text of this Article]