Thrombosis and Haemostasis 103.5/2010 1 © Schattauer 2010 Theme Issue Article Thrombin receptors in vascular smooth muscle cells – function and regulation by vasodilatory prostaglandins Karsten Schrör 1 ; Ellen Bretschneider 2 ; Kerstin Fischer 3 ; Jens W. Fischer 4 ; Robert Pape 5 ; Bernhard H. Rauch 1 ; Anke C. Rosenkranz 1 ; Artur-Aron Weber 6 1 Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany; 2 Molekulare Hämostaseologie, Universität Jena, Jena, Germany; 3 Bristol-Myers Squibb, München, Germany; 4 Institut fuer Pharmakologie, Universitaetsklinikum Essen, Essen, Germany; 5 Maubishof-Apotheke, Kaarst, Germany; 6 Klinik für Allgemeine Pädiatrie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany Summary The vast majority of thrombin (>95%) is generated after clotting is completed, suggesting that thrombin formation serves purposes beyond coagulation, such as tissue repair after vessel injury. Two types of vascular thrombin binding sites exist: protease-activated receptors (PARs) and thrombomodulin (TM). Their expression is low in contractile vascular smooth muscle cells (SMC), the dominating subendothelial cell population, but becomes markedly up-regulated upon injury. In human SMC, PAR-1, PAR-3, and PAR-4 mediate thrombin-induced pro- liferation, migration and matrix biosynthesis as well as generation of inflammatory and growth-promoting mediators. Thrombin-responsive PARs are transcriptionally down-regulated in human vascular SMC by vasodilatory prostaglandins (PGI 2 /PGE 2 ). For PAR-1 and PAR-3 this mechanism involves cAMP-dependent inactivation of the transcription factor NFAT. The human PAR-4 promoter does not possess NFAT recog- nition motifs suggesting involvement of other cAMP-regulated effec- Correspondence to: Prof. Karsten Schrör Institut für Pharmakologie und Klinische Pharmakologie Universitätsklinikum Düsseldorf Universitätsstraße 1, Gebäude 22.21 40225 Düsseldorf, Germany, Tel.: +49 211 81 12500, Fax: +49 211 81 14781 E-mail: karsten.schroer@uni-duesseldorf.de tors. Unlike PARs, TM is induced in SMC exposed to vasodilatory pros- taglandins. Enhanced thrombin binding to TM might ameliorate PAR- mediated SMC stimulation. Also expressed in human SMC is the en- dothelial protein C receptor (EPCR), which serves as an anchor to facili- tate generation of activated protein C (aPC) by TM-bound thrombin. Whether prostaglandins affect aPC-generation is not known. In SMC, thrombin and aPC act synergistically via PAR-1 to modify tissue remod- elling, in contrast to their antagonistic interaction in the coagulation pathways. Overall, this will contribute to plaque stability and wound healing. The processes outlined here are likely to become clinically rel- evant after up-regulation of vascular cyclooxygenase2, the rate limiting step in vascular PGE 2 /PGI 2 biosynthesis, such as in advanced athero- sclerosis and acute coronary syndromes. Keywords Prostaglandins, thrombin, thrombomodulin, PAR, smooth muscle cell Received: September 7, 2009 Accepted after major revision: December 6, 2009 Prepublished online: February 8, 2010 doi:10.1160/TH09-09-0627 Thromb Haemost 2010; 103: ■■■ Introduction Generation of thrombin from its zymogen prothrombin is the critical step of the clotting process, culminating in the generation of a platelet/fibrin thrombus and its fixation to the injured area of the vessel wall. Thrombus formation indicates that bleeding has been successfully stopped by the concerted actions of clotting fac- tors, which incidentally are the same in both physiological and pathological haemostasis (thrombosis). However, in both situ- ations, plug formation is not the true end of the haemostatic pro- cess. Vessel injury, specifically the local loss of endothelium and other structural elements required for sealing the vessel against blood loss, still persists. This damage must be repaired to allow for restoration of blood flow and recovery of antithrombotic/vasodi- lator properties of the vessel lining, in the optimal case, a restitutio ad integrum. This review discusses recent finding which shed further light on how these events are regulated, namely the tran- scriptional control of thrombin receptor expression by the vasodi- latory prostaglandins prostacyclin (PGI 2 ) and PGE 2 . Thrombin and the clotting process Endothelial injury is associated with loss of barrier function and penetration of clotting factors into the subendothelium. This allows direct contact of tissue-factor bearing cells, such as sub- endothelial smooth muscle cells (SMC) and fibroblasts, with the thrombus and components of the streaming blood. The immediate consequence is the activation of the coagulation cascade. In this context, it should be noted that only a small proportion of throm- bin, about 0.2% of total, is actually generated during the initiation For personal or educational use only. No other uses without permission. All rights reserved. Downloaded from www.thrombosis-online.com on 2017-06-19 | IP: 54.191.40.80