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

Abstract

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 prostaglandins. 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.

Endothelium and Its Alterations in Cardiovascular Diseases: Life Style Intervention

“…This process involves a complex interplay between intracellular receptors, the synthesis, and then the release of a variety of endothelium-derived relaxing and constricting substances [119, 120]. …”

Sphingosine 1-Phosphate as a Link between Blood Coagulation and Inflammation

“…Thrombin and FXa regulate many genes in vascular smooth muscle cells, including those for inflammatory cytokines and cell proliferation [8,9,10]. These transcriptional effects on gene regulation and subsequent cellular reactions are partially due to the recruitment of additional signaling systems, i.e.…”

“…Consequently, inhibitors of thrombin and/or FXa attenuate inflammatory and proliferative responses in vascular cells in experimental settings [8]. These cellular effects of thrombin and FXa are mediated independently of each other via a family of G-protein coupled receptors, the protease-activated receptors-1, -2, -3 and -4 (PAR-1 to PAR-4) [9,10]. While thrombin acts via PAR-1, PAR-2 and PAR-4, FXa can initiate signaling through PAR-1 and PAR-2.…”

“…PARs are ubiquitously expressed in platelets, white blood cells and cells of the vasculature [10,12]. In the vessel wall, PARs stimulate smooth muscle cell proliferation and migration, modify the composition of the extracellular matrix of blood vessels, and mediate proinflammatory responses [8,9,13,14]. Because proliferation and migration of smooth muscle cells are considered key events in the development of atherosclerosis and vascular remodeling, these cellular effects of thrombin and FXa may directly contribute to the pathogenesis of vascular diseases such as progression of atherosclerosis and restenosis after vascular injury [6,15,16].…”

Evaluation on Potential Contributions of Protease Activated Receptors Related Mediators in Allergic Inflammation

“…PAR-1, -3, and -4 are able to mediate thrombin-induced proliferation, migration, and matrix biosynthesis as well as generation of inflammatory and growth-promoting mediators in human vascular SMCs [75]. …”