doi: 10.1161/01.RES.0000269328.78313.26
© 2007 American Heart Association, Inc.
Letters to the Editor |
The Endothelial Protein C Receptor in Vascular Smooth Muscle Cells For Good or Bad?
Department of Molecular and Experimental Medicine, Department of Immunology, The Scripps Research Institute, La Jolla, California
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 has a very short intracellular C-terminal tail, many consider it unlikely that EPCR alone triggers any intracellular signaling. Secondly, does APC-ligated EPCR activate other cellular receptors in VSMCs? Experiments show that EPCR ligation with APC can transactivate the sphingosine-1-phosphate receptor-1 in ECs.6,7
Bretschneider et al1 also demonstrated the expression of EPCR in the fibrous cap of human artery plaques, an area rich in VSMC, and suggested that EPCR-mediated signaling might regulate VSMC in atherosclerosis. Rupture of atherosclerotic plaques can trigger acute coronary events, such as myocardial infarction and stroke. Plaque rupture generally occurs in the "shoulder regions" of advanced plaques with thin fibrous caps, often called unstable or vulnerable plaques.9,10 The VSMCs of the fibrous cap in advanced plaques might be exposed to plasma proteins from increased endothelial permeability. Thus, EPCR might trigger VSMC proliferation, and might also alter VSMC production of extra-cellular matrix and matrix metalloproteinases, altering plaque vulnerability. We would like to suggest that further studies should evaluate the effects of EPCR on atherosclerosis and plaque vulnerability.
References
1. Bretschneider E, Uzonyi B, Weber AA, Fischer JW, Pape R, Lotzer K, Schror K. Human vascular smooth muscle cells express functionally active endothelial cell protein C receptor. Circ Res. 2007; 100: 255–262.
2. Liu D, Cheng T, Guo H, Fernandez JA, Griffin JH, Song X, Zlokovic BV. Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Nat Med. 2004; 10: 1379–1383.[CrossRef][Medline] [Order article via Infotrieve]
3. Cheng T, Liu D, Griffin JH, Fernandez JA, Castellino F, Rosen ED, Fukudome K, Zlokovic BV. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med. 2003; 9: 338–342.[CrossRef][Medline] [Order article via Infotrieve]
4. Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science. 2002; 296: 1880–1882.
5. Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW. Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem. 2001; 276: 11199–11203.
6. Feistritzer C, Riewald M. Endothelial barrier protection by activated protein C through PAR-1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood. 2005; 105: 3178–3184.
7. Finigan JH, Dudek SM, Singleton PA, Chiang ET, Jacobson JR, Camp SM, Ye SQ, Garcia JG. Activated protein C mediates novel lung endothelial barrier enhancement: role of sphingosine 1-phosphate receptor transactivation. J Biol Chem. 2005; 280: 17286–17293.
8. Uchiba M, Okajima K, Oike Y, Ito Y, Fukudome K, Isobe H, Suda T. Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo. Circ Res. 2004; 95: 34–41.
9. Weissberg PL, Clesham GJ, Bennett MR. Is vascular smooth muscle cell proliferation beneficial? Lancet. 1996; 347: 305–307.[CrossRef][Medline] [Order article via Infotrieve]
10. Clarke MC, Figg N, Maguire JJ, Davenport AP, Goddard M, Littlewood TD, Bennett MR. Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nat Med. 2006; 12: 1075–1080.[CrossRef][Medline] [Order article via Infotrieve]
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