Thrombin receptors in vascular smooth muscle cells – function and regulation by vasodilatory prostaglandins

Karsten Schrör; Ellen Bretschneider; Kerstin Fischer; Jens W. Fischer; Robert Pape; Bernhard H. Rauch; Anke C. Rosenkranz; Artur-Aron Weber

doi:10.1160/TH09-09-0627

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 103(05): 884-890
DOI: 10.1160/TH09-09-0627

Theme Issue Article

Schattauer GmbH

Thrombin receptors in vascular smooth muscle cells – function and regulation by vasodilatory prostaglandins

Karsten Schrör

¹Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany

,

Ellen Bretschneider

²Molekulare Hämostaseologie, Universität Jena, Jena, Germany

,

Kerstin Fischer

³Bristol-Myers Squibb, München, Germany

,

Jens W. Fischer

⁴Institut fuer Pharmakologie, Universitaetsklinikum Essen, Essen, Germany

,

Robert Pape

⁵Maubishof-Apotheke, Kaarst, Germany

,

Bernhard H. Rauch

¹Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany

,

Anke C. Rosenkranz

¹Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany

,

Artur-Aron Weber

⁶Klinik für Allgemeine Pädiatrie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany

› Author Affiliations

Abstract

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 proliferation, 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 (PGI₂/PGE₂). 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 recognition motifs suggesting involvement of other cAMP-regulated effectors. 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 endothelial protein C receptor (EPCR), which serves as an anchor to facilitate 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 remodelling, 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 relevant after up-regulation of vascular cyclooxygenase2, the rate limiting step in vascular PGE₂/PGI₂ biosynthesis, such as in advanced atherosclerosis and acute coronary syndromes.

Keywords

Prostaglandins - thrombin - thrombomodulin - PAR - smooth muscle cell

Full Text

References

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