The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

Abstract

Abstract-Proteinase-activated receptors (PARs) belong to a family of G protein-coupled receptors, thus mediating the cellular effects of proteinases. In the vascular system, thrombin and other proteinases in the coagulation-fibrinolysis system are considered to be the physiologically relevant agonists, whereas PARs are among the most important mechanisms mediating the interaction between the coagulation-fibrinolysis system and the vascular wall. Under physiological conditions, PARs are mainly expressed in endothelial cells, and participate in the regulation of vascular tone, mostly by inducing endothelium-dependent relaxation. PARs in endothelial cells are also suggested to contribute to a proinflammatory phenotypic conversion and an increase in the permeability of vascular lesions. In smooth muscle cells, PARs mediate contraction, migration, proliferation, hypertrophy, and production of the extracellular matrix, thereby contributing to the development of vascular lesions and the pathophysiology of such vascular diseases as atherosclerosis. However, the expression of PARs in the smooth muscle of normal arteries is limited. The upregulation of PARs in the smooth muscle is thus considered to be a key step for PARs to participate in the pathogenesis of vascular lesions. Elucidating the molecular mechanism regulating the PARs expression is therefore important to develop new strategies for the prevention and treatment of vascular diseases. (Arterioscler Thromb Vasc Biol. 2007;27:27-36.)

Up‐regulation of proteinase‐activated receptor 1 and increased contractile responses to thrombin after subarachnoid haemorrhage

“…However, the expression of PAR 1 in smooth muscle has been shown to be upregulated in vascular lesions such as those seen in atherosclerosis (Nelken et al, 1992;Ku and Dai, 1997) and balloon injury models (Wilcox et al, 1994;Fukunaga et al, 2006). Such upregulation of PAR 1 expression in smooth muscle is thus considered to play a critical step in the development of vascular lesions and hyper-contractile state (Hirano, 2007). In this respect, the present study provides the first evidence that the expression of PAR 1 was upregulated after SAH.…”

“…Under physiological conditions, PAR 1 is mainly expressed in vascular endothelial cells, while its expression in smooth muscle is limited (Hirano, 2007). However, the expression of PAR 1 in smooth muscle has been shown to be upregulated in vascular lesions such as those seen in atherosclerosis (Nelken et al, 1992;Ku and Dai, 1997) and balloon injury models (Wilcox et al, 1994;Fukunaga et al, 2006).…”

G Protein-Coupled Receptor Dependent NF-κB Signaling in Atherogenesis

“…As discussed earlier, thrombin and its receptor, PAR-1, are thought to induce a variety of pro-inflammatory responses that may also contribute to endothelial phenotype changes (Hirano, 2007). Thrombin levels are increased at sites of vascular injury and thrombosis, where the persistent stimulation of its receptor leads to endothelial dysfunction, thereby increasing inflammatory responses leading to further vessel wall damage and atherosclerotic lesion progression.…”

“…A synthetic peptide with the same SFLLRN sequence, also known as TRAP-6, can be used to induce the same response from PAR-1 as thrombin (Coughlin, 2005). Both PAR-1 and its agonist thrombin are major participants in the regulation of endothelial cell biology and atherogenesis, affecting cell signaling, gene expression, endothelial permeability, angiogenesis, and vascular tone (Hirano, 2007). Indeed, the importance of direct pro-atherogenic effects of thrombin on cells of the vessel wall were recently highlighted by a study in mice showing that atherosclerosis can proceed independently of thrombin-induced platelet activation (Hamilton et al, 2009).…”

Plasma heparin cofactor II activity is inversely associated with left atrial volume and diastolic dysfunction in humans with cardiovascular risk factors

“…Thrombin exerts its physiological and pathological actions in these cells through the proteolytic processing of specific cell-surface receptors known as protease-activated receptors (PARs). 5,6 Nelken et al 7 demonstrated that PAR-1 was widely expressed in regions where macrophages, cardiomyocytes, cardiac fibroblasts, vascular smooth muscle cells and mesenchymal-appearing intimal cells are abundantly present. Thus, excessive PAR-1 activation promotes cardiovascular disorders, including cardiac remodeling, arterial thrombosis and atherosclerosis.…”