Physiology, pharmacology, and therapeutic potential of protease-activated receptors in vascular disease

It has been 20 years since the discovery of the prototypical protease-activated receptor (PAR). In the time since this landmark work, significant advances have been made in our understanding of this family of four G protein-coupled receptors. Initially discovered and characterized in an attempt to determine the mechanism by which thrombin activates platelets, PARs have since been found to be widely expressed throughout the body, respond to multiple proteases, and to be involved in a vast array of physiological processes. Yet despite their wide-ranging expression, the function of PARs has been most extensively studied in the vascular system. In particular, the importance of PAR1 for platelet activation during arterial thrombosis has been thoroughly investigated and has led to the development of a host of PAR1 antagonists—two of which are currently in Phase 3 trials as antiplatelet agents. Given the impending clinical use of the first PAR antagonists, it is timely to review the physiological roles of PARs in cells of the blood and blood vessels, the development and experimental use of PAR antagonists in these systems, and the potential clinical application of these agents as therapeutics for vascular diseases.