Hemostatic protease receptors and endothelial cell function: insights from gene targeting in mice

Hemostasis constitutes a major defense system of our body that maintains blood flow in the circulation and prevents life-threatening blood loss. The endothelium plays a crucial dynamic role as a protective interface between blood and the underlying tissues during this process. Following vessel wall injury with initial platelet adhesion and aggregation to exposed subendothelial extracellular matrix, the initiation, amplification, and control of hemostasis depend on structurally unrelated membrane-associated receptors for blood coagulation proteases including tissue factor, G protein-coupled protease-activatable receptors, thrombomodulin, or protein C receptor. In addition to their regulatory role in hemostasis, the respective (pro-)enzyme ligands such as factors VIIa and Xa, thrombin, and protein C mediate specific signaling pathways in vascular cells related to migration, proliferation, or adhesion. The functional importance of these receptors beyond hemostasis has been manifested by various lethal or pathological phenotypes in knock-out mice. These protease receptors thereby provide important molecular links in the vascular system and serve to integrate hemostasis with endothelial cell functions that are relevant for the (patho-) physiological responses to inflammatory challenges, injury, or infection.