title: Extraembryonic expression of EPCR is essential for embryonic viability.
abstract: The endothelial cell protein C receptor (EPCR) augments protein C activation by the thrombin-thrombomodulin complex. Deletion of the EPCR gene (Procr) in mice leads to embryonic lethality before embryonic day 10 (E10.0). EPCR is detected in the giant trophoblast cells at the feto-maternal boundary from E7.5 and weakly in embryonic aortic endothelial cells from E13.5, suggesting that extraembryonic EPCR expression may be essential for embryonic viability. Using conditional knock-out strategies, we demonstrate that Procr-deficient embryos with EPCR expression on placenta giant trophoblasts can be carried to term and then develop normally. Conversely, EPCR expression in the embryo, without expression in the giant trophoblast cells, does not rescue the mice. In genetically modified mice with low tissue factor activity, Procr deficiency is not lethal to the embryo. As adults, Procr-deficient mice generate more thrombin and activate less protein C in response to procoagulant stimuli. Spontaneous thrombin formation in the deficient animals increases with age. These findings show that extraembryonic EPCR expression is critical for embryo development.
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Weihong
authors.initials: W
authors.lastname: Li
authors.forename: Xunzhen
authors.initials: X
authors.lastname: Zheng
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Gu
authors.forename: Gary L
authors.initials: GL
authors.lastname: Ferrell
authors.forename: Mingming
authors.initials: M
authors.lastname: Brady
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Esmon
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001779:Blood Coagulation Factors / Q000235:genetics / Q000378:metabolism*; D020964:Embryo Loss / Q000235:genetics; D004622:Embryo, Mammalian / Q000196:embryology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013925:Thromboplastin / Q000172:deficiency / Q000235:genetics; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D001779:Blood Coagulation Factors; D011956:Receptors, Cell Surface; C091963:activated protein C receptor; D013925:Thromboplastin