title: Characterization of mice harboring a variant of EPCR with impaired ability to bind protein C: novel role of EPCR in hematopoiesis.
abstract: The interaction of protein C (PC) with the endothelial PC receptor (EPCR) enhances activated PC (APC) generation. The physiological importance of EPCR has been demonstrated in EPCR knockout mice which show early embryonic lethality due to placental thrombosis. In order to study the role of EPCR independent of PC interaction, we generated an EPCR point mutation knock-in mouse (EPCR(R84A/R84A)) which lacks the ability to bind PC/APC. EPCR(R84A/R84A) mice are viable and reproduce normally. In response to thrombotic challenge with factor Xa/phospholipids, EPCR(R84A/R84A) mice generate more thrombin, less APC, and show increased fibrin deposition in lungs and heart compared with wild-type (WT) mice. EPCR(R84A/R84A) mice challenged with lipopolysaccharide generate less APC, more interleukin-6, and show increased neutrophil infiltration in the lungs compared with WT controls. Interestingly, EPCR(R84A/R84A) mice develop splenomegaly as a result of bone marrow (BM) failure. BM transplant experiments suggest a role for EPCR on hematopoietic stem cells and BM stromal cells in modulating hematopoiesis. Taken together, our studies suggest that impaired EPCR/PC-binding interactions not only result in procoagulant and proinflammatory effects, but also impact hematopoiesis.
authors.affiliation: Department of Medical Sciences, McMaster University, Hamilton, ON, Canada; Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada; and.
authors.forename: Laura
authors.initials: L
authors.lastname: Pepler
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada; and Department of Biochemistry and Biomedical Science, and.
authors.forename: Pei
authors.initials: P
authors.lastname: Yu
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada; and Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Dhruva J
authors.initials: DJ
authors.lastname: Dwivedi
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada; and Department of Biochemistry and Biomedical Science, and.
authors.forename: Bernardo L
authors.initials: BL
authors.lastname: Trigatti
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada; and Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Liaw
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000990:Antithrombin III / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002460:Cell Line; D000074283:Endothelial Protein C Receptor; D005260:Female; D006410:Hematopoiesis / Q000235:genetics* / Q000502:physiology*; D007249:Inflammation / Q000097:blood / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D011485:Protein Binding; D011486:Protein C / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D013163:Splenomegaly / Q000097:blood / Q000209:etiology / Q000235:genetics; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000235:genetics
chemical_list: D000074283:Endothelial Protein C Receptor; D050505:Mutant Proteins; C080248:Procr protein, mouse; D011486:Protein C; D011956:Receptors, Cell Surface; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D010447:Peptide Hydrolases