Subscribe to RSS
DOI: 10.1160/TH09-09-0627
Thrombin receptors in vascular smooth muscle cells – function and regulation by vasodilatory prostaglandins
Publication History
Received:
07 September 2009
Accepted after major revision:
06 February 2009
Publication Date:
22 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201005/lookinside/thumbnails/10-1160-th09-09-0627-1.jpg)
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.
-
References
- 1 Brummel KE. et al. Thrombin functions during tissue factor-induced blood coagulation. Blood 2002; 100: 148-152.
- 2 Mutch NJ. et al. Human thrombi contain an abundance of active thrombin. Thromb Haemost 2001; 86: 1028-1034.
- 3 Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264: 4743-4746.
- 4 Tollefsen DM. Heparin cofactor II modulates the response to vascular injury. Arterioscler Thromb Vasc Biol 2007; 27: 454-460.
- 5 McBane RD. et al. Tissue prothrombin. Universal distribution in smooth muscle. Arterioscler Thromb Vasc Biol 1997; 17: 2430-2436.
- 6 Mackman N. The role of the tissue factor-thrombin pathway in cardiac ischemiareperfusion injury. Semin Vasc Med 2003; 03: 193-198.
- 7 Bretschneider E. et al. Factor Xa acts as a PDGF-independent mitogen in human vascular smooth muscle cells. Thromb Haemost 2000; 84: 499-505.
- 8 Marmur JD. et al. Thrombin generation in human coronary arteries after percutaneous transluminal balloon angioplasty. J Am Coll Cardiol 1994; 24: 1484-1491.
- 9 Bar-Shavit R. et al. Binding of thrombin to subendothelial extracellular matrix. Protection and expression of functional properties. J Clin Invest 1989; 84: 1096-1104.
- 10 Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407: 258-264.
- 11 Hirano K. The roles of proteinase-activated receptors in the vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol 2007; 27: 27-36.
- 12 Martorell L. et al. Thrombin and protease-activated receptors (PARs) in atherothrombosis. Thromb Haemost 2008; 99: 305-315.
- 13 Bretschneider E. et al. Evidence for functionally active protease-activated receptor-4 (PAR-4) in human vascular smooth muscle cells. Br J Pharmacol 2001; 132: 1441-1446.
- 14 Bretschneider E. et al. Evidence for functionally active protease-activated receptor-3 (PAR-3) in human vascular smooth muscle cells. Thromb Haemost 2003; 90: 704-709.
- 15 Steinberg SF. The cardiovascular actions of protease-activated receptors. Mol Pharmacol 2005; 67: 2-11.
- 16 Nelken NA. et al. Thrombin receptor expression in normal and atherosclerotic human arteries. J Clin Invest 1992; 90: 1614-1621.
- 17 Li F. et al. Cloning and identification of regulatory sequences of the human thrombin receptor gene. J Biol Chem 1996; 271: 26320-26328.
- 18 Wilcox JN. et al. Characterization of thrombin receptor expression during vascular lesion formation. Circ Res 1994; 75: 1029-1038.
- 19 DeBault LE. et al. Distribution of the thrombomodulin antigen in the rabbit vasculature. Lab Invest 1986; 54: 172-178.
- 20 Fink LM. et al. Thrombomodulin activity and localization. Int J Dev Biol 1993; 37: 221-226.
- 21 Chamley-Campbell J. et al. The smooth muscle cell in culture. Physiol Rev 1979; 59: 1-61.
- 22 Soff GA. et al. Expression of thrombomodulin by smooth muscle cells in culture: different effects of tumor necrosis factor and cyclic adenosine monophosphate on thrombomodulin expression by endothelial cells and smooth muscle cells in culture. Blood 1991; 77: 515-518.
- 23 Ma SF. et al. Thrombin induces thrombomodulin mRNA expression via the proteolytically activated thrombin receptor in cultured bovine smooth muscle cells. J Lab Clin Med 1997; 129: 611-619.
- 24 Rabausch K. et al. Regulation of thrombomodulin expression in human vascular smooth muscle cells by COX-2-derived prostaglandins. Circ Res 2005; 96: e1-6.
- 25 Grinnell BW, Berg DT. Surface thrombomodulin modulates thrombin receptor responses on vascular smooth muscle cells. Am J Physiol 1996; 270: H603-609.
- 26 Kainoh M. et al. Enhancement by beraprost sodium, a stable analogue of pros-tacyclin, in thrombomodulin expression on membrane surface of cultured vascular endothelial cells via increase in cyclic AMP level. Biochem Pharmacol 1991; 41: 1135-1140.
- 27 DeWitt DL. et al. Concentrations of prostaglandin endoperoxide synthase and prostaglandin I2 synthase in the endothelium and smooth muscle of bovine aorta. J Clin Invest 1983; 72: 1882-1888.
- 28 Rimarachin JA. et al. Regulation of cyclooxygenase-2 expression in aortic smooth muscle cells. Arterioscler Thromb 1994; 14: 1021-1031.
- 29 Raines EW, Ross R. Smooth muscle cells and the pathogenesis of the lesions of atherosclerosis. Br Heart J 1993; 69 (Suppl. 01) S30-37.
- 30 Fischer JW, Schrör K. Regulation of hyaluronan synthesis by vasodilatory prostaglandins. Implications for atherosclerosis. Thromb Haemost 2007; 98: 287-295.
- 31 Pape R. et al. Transcriptional inhibition of protease-activated receptor-1 expression by prostacyclin in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2008; 28: 534-540.
- 32 Rosenkranz AC. et al. Regulation of protease-activated receptor-1 by vasodilatory prostaglandins via NFAT. Cardiovasc Res 2009; 83: 778-784.
- 33 Rosenkranz AC. et al. Iloprost transcriptionally regulates protease-activated receptor-3 (PAR-3) in human vascular smooth muscle cells. Proc Br Pharmacol Soc 2009; 07: 55.
- 34 Sokolova E. et al. Protease-activated receptor-1 in human lung fibroblasts mediates a negative feedback downregulation via prostaglandin E2. Am J Physiol Lung Cell Mol Physiol 2005; 288: L793-802.
- 35 Sheridan CM. et al. Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1 by priming for subsequent phosphorylation by glycogen synthase kinase-3. J Biol Chem 2002; 277: 48664-48676.
- 36 Liu Z. et al. Blockade of nuclear factor of activated T cells activation signaling suppresses balloon injury-induced neointima formation in a rat carotid artery model. J Biol Chem 2005; 280: 14700-14708.
- 37 Macian F. et al. Partners in transcription: NFAT and AP-1. Oncogene 2001; 20: 2476-2489.
- 38 Freedman JE. Thrombin, thrombomodulin, and extracellular signal-regulated kinases regulating cellular proliferation. Circ Res 2001; 88: 651-653.
- 39 Li J. et al. Recombinant thrombomodulin inhibits arterial smooth muscle cell proliferation induced by thrombin. J Vasc Surg 2000; 32: 804-813.
- 40 Tohda G. et al. Expression of thrombomodulin in atherosclerotic lesions and mitogenic activity of recombinant thrombomodulin in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1998; 18: 1861-1869.
- 41 Ludeman MJ. et al. PAR1 cleavage and signaling in response to activated protein C and thrombin. J Biol Chem 2005; 280: 13122-13128.
- 42 Bretschneider E. et al. Human vascular smooth muscle cells express functionally active endothelial cell protein C receptor. Circ Res 2007; 100: 255-262.
- 43 Kanthou C. et al. Involvement of pertussis toxin-sensitive and -insensitive G proteins in alpha-thrombin signalling on cultured human vascular smooth muscle cells. Cell Signal 1996; 08: 59-66.
- 44 Andrade-Gordon P. et al. Administration of a potent antagonist of protease-activated receptor-1 (PAR-1) attenuates vascular restenosis following balloon angioplasty in rats. J Pharmacol Exp Ther 2001; 298: 34-42.
- 45 Belton O. et al. Cyclooxygenase-1 and –2-dependent prostacyclin formation in patients with atherosclerosis. Circulation 2000; 102: 840-845.
- 46 Schrör K. et al. Obligatory role of cyclic adenosine monophosphate response element in cyclooxygenase-2 promoter induction and feedback regulation by inflammatory mediators. Circulation 2002; 105: 2760-2765.
- 47 Subramanian VA. et al. Prostacyclin production by internal mammary artery as a factor in coronary artery bypass grafts. Surgery 1986; 100: 376-383.
- 48 Yang Z. et al. Different proliferative properties of smooth muscle cells of human arterial and venous bypass vessels: role of PDGF receptors, mitogen-activated protein kinase, and cyclin-dependent kinase inhibitors. Circulation 1998; 97: 181-187.
- 49 Yu H. et al. Therapeutic potential of a synthetic peptide inhibitor of nuclear factor of activated T cells as antirestenotic agent. Arterioscler Thromb Vasc Biol 2006; 26: 1531-1537.