Role of the Endothelium in the Vascular Effects of the Thrombin Receptor (Protease-Activated Receptor Type 1) in Humans

Abstract

Acting via PAR-1, thrombin causes contrasting effects in the human vasculature and has a major interaction with the endothelium. This highlights the critical importance of endothelial function during acute arterial injury and intravascular thrombosis, as occurs in cardiovascular events including myocardial infarction and stroke.

Clinical Implications of the Contrasting Effects of In Vivo Thrombin Receptor Activation (Protease-Activated Receptor Type 1) on the Human Vasculature⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

“…In this issue of the Journal, Gu mundsdóttir et al (9) confirm and extend their observations describing the selective effects PAR-1 activation in vivo in humans. The endothelium regulates the tone of vascular smooth muscle via production of endogenous vasodilators.…”

“…The endotheliumderived relaxing factors (EDRF) include nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), and prostacyclin. Gu mundsdóttir et al (9) show that PAR-1-dependent arterial vasodilatation is dependent on the endothelium, because inhibition of NO and EDHF nearly completely attenuated the vasodilator response (Fig. 1).…”

Marked Impairment of Protease-Activated Receptor Type 1-Mediated Vasodilation and Fibrinolysis in Cigarette Smokers

“…This increase in PAI-1 antigen without a change in activity suggests that SFLLRN is releasing PAI-1 from platelets rather than the endothelium because plateletderived PAI-1 is relatively inactive as a result of the absence of the stabilizing effects of vitronectin (16,21). Furthermore, our own recent work has demonstrated a concomitant increase in beta-thromboglobulin, suggesting degranulation of platelet alpha granules (22). Therefore, the contribution of the endogenous fibrinolytic system to the prothrombotic state found in cigarette smokers is likely to be driven by impaired endothelial t-PA release and not by alterations in PAI-1 release or activity.…”

Dabigatran etexilate: Another Double-Edged Drug?

“…By exerting pro-inflammatory actions, thrombin may modulate the formation of atherosclerotic lesions in several phases of this complex process. Thus, in initial stages of atherosclerosis thrombin may act as an inductor of endothelial dysfunction [10,11], increasing the permeability of the endothelial barrier [12,13] and inducing the adhesion and transmigration of leukocytes by increasing the expression of leukocyte adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1(ICAM-1) and E-selectin [14][15][16] and chemokines such as monocyte chemoattractant protein-1 (MCP-1) in endothelial cells [17]. In more advanced stages, lesions grow by migration of new inflammatory cells, proliferation of smooth muscle cells and extracellular lipid accumulation, and they finally are covered by a fibrous cap consisting of smooth muscle cells and extracellular matrix.…”