ACTIVATION MECHANISM OF ANTICOAGULANT PROTEIN-C IN LARGE BLOOD-VESSELS INVOLVING THE ENDOTHELIAL-CELL PROTEIN-C RECEPTOR

Protein C is an important regulatory mechanism of blood coagulation. P rotein C functions as an anticoagulant when converted to the active se rine protease form on the endothelial cell surface. Thrombomodulin (TM ), an endothelial cell surface receptor specific for thrombin, has bee n identified as an essential component for protein C activation. Altho ugh protein C can be activated directly by the thrombin-TM complex, th e conversion is known as a relatively low-affinity reaction. Therefore , protein C activation has been believed to occur only in microcircula tion. On the other hand, we have identified and cloned a novel endothe lial cell surface receptor (EPCR) that is capable of high-affinity bin ding of protein C and activated protein C. In this study, we demonstra te the constitutive, endothelial cell-specific expression of EPCR in v ivo. Abundant expression was particularly detected in the aorta and la rge arteries. In vitro cultured, arterial endothelial cells were also found to express abundant EPCR and were capable of promoting significa nt levels of protein C activation. EPCR was found to greatly accelerat e protein C activation by examining functional activity in transfected cell lines expressing EPCR and/or TM. EPCR decreased the dissociation constant and increased the maximum velocity for protein C activation mediated by the thrombin-TM complex. By these mechanisms, EPCR appears to enable significant levels of protein C activation in large vessels . These results suggest that the protein C anticoagulation pathway is important for thr regulation of blood coagulation not only in microves sels but also in large vessels.