The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/4/1029/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 7, April 6, 1998 1029-1035

Articles

Activation Mechanism of Anticoagulant Protein C in Large Blood Vessels Involving the Endothelial Cell Protein C Receptor

Kenji Fukudome*, Xiaofen Ye*, Naoko Tsuneyoshi*, Osamu Tokunaga{ddagger}, Keishin Sugawara§, Hiroshi Mizokami§, and Masao Kimoto*

From the * Department of Immunology and the {ddagger} Department of Pathology, Saga Medical School, Nabeshima, Saga 849, Japan; and the § Applied Research Laboratory, The Chemo-Sero-Therapeutic Research Institute, Shimizu, Kumamoto 860, Japan

Protein C is an important regulatory mechanism of blood coagulation. Protein C functions as an anticoagulant when converted to the active serine protease form on the endothelial cell surface. Thrombomodulin (TM), an endothelial cell surface receptor specific for thrombin, has been identified as an essential component for protein C activation. Although protein C can be activated directly by the thrombin–TM complex, the conversion is known as a relatively low-affinity reaction. Therefore, protein C activation has been believed to occur only in microcirculation. On the other hand, we have identified and cloned a novel endothelial cell surface receptor (EPCR) that is capable of high-affinity binding of protein C and activated protein C. In this study, we demonstrate the constitutive, endothelial cell–specific expression of EPCR in vivo. Abundant expression was particularly detected in the aorta and large arteries. In vitro cultured, arterial endothelial cells were also found to express abundant EPCR and were capable of promoting significant levels of protein C activation. EPCR was found to greatly accelerate 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 the regulation of blood coagulation not only in microvessels but also in large vessels.

Address correspondence to Kenji Fukudome, Department of Immunology, Saga Medical School, 5-1-1 Nabeshima, Saga 849, Japan. Phone: 81-952-34-2256; Fax: 81-952-34-2049; E-mail: fukudome{at}post.saga-med.ac.jp

1Abbreviations used in this paper: AEC, arterial endothelial cell; APC, activated protein C; EPCR, endothelial cell protein C-APC receptor; TM, thrombomodulin; VEC, venous endothelial cell.


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