Blood platelet and endothelial Protease-Activated Receptor-1 in hemostasis and thrombosis.

Protease activated receptors (PAR) on platelets trigger potent platelet activation when activated by thrombin, according to a unique mechanism. The relative importance of PAR1 and PAR4 for platelet activation is studied in platelets of different species with different PAR subtype receptor expression and in PAR4 gene-deficient mice, focusing on intracellular pathways of platelet activation. Contribution of murine platelet PAR4 activation to thrombus formation is investigated in thrombosis and embolization models, in relation to coagulation activation and thrombin formation. The relative importance of platelet PAR activation will be investigated in a chronic model of hypoxia-induced tissue factor upregulation and pulmonary platelet-rich thrombosis, by exposing wt and PAR4 knock-out mice to hypoxia, in parallel. Because mouse platelets lack PAR1, the simultaneous inhibition of PAR1, present in endothelium, will assess the risk of chronic endothelial PAR1 inhibition, in this semi-chronic model of thrombosis.

Keywords:thrombosis, endothelium, PAR, Thrombin

Disciplines:Physiology, Systems biology, Hematology, Laboratory medicine, Cardiac and vascular medicine