title: Lack of protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis.
abstract: Protein S (ProS) is a blood anticoagulant encoded by the Pros1 gene, and ProS deficiencies are associated with venous thrombosis, stroke, and autoimmunity. These associations notwithstanding, the relative risk that reduced ProS expression confers in different disease settings has been difficult to assess without an animal model. We have now described a mouse model of ProS deficiency and shown that all Pros1-/- mice die in utero,from a fulminant coagulopathy and associated hemorrhages. Although ProS is known to act as a cofactor for activated Protein C (aPC), plasma from Pros1+/- heterozygous mice exhibited accelerated thrombin generation independent of aPC, and Pros1 mutants displayed defects in vessel development and function not seen in mice lacking protein C. Similar vascular defects appeared in mice in which Pros1 was conditionally deleted in vascular smooth muscle cells. Mutants in which Pros1 was deleted specifically in hepatocytes, which are thought to be the major source of ProS in the blood, were viable as adults and displayed less-severe coagulopathy without vascular dysgenesis. Finally, analysis of mutants in which Pros1 was deleted in endothelial cells indicated that these cells make a substantial contribution to circulating ProS. These results demonstrate that ProS is a pleiotropic anticoagulant with aPC-independent activities and highlight new roles for ProS in vascular development and homeostasis.
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California, USA.
authors.forename: Tal
authors.initials: T
authors.lastname: Burstyn-Cohen
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Heeb
authors.forename: Greg
authors.initials: G
authors.lastname: Lemke
mesh_terms: D000818:Animals; D001775:Blood Circulation; D001777:Blood Coagulation; D001778:Blood Coagulation Disorders / Q000196:embryology* / Q000473:pathology / Q000503:physiopathology*; D001808:Blood Vessels / Q000002:abnormalities / Q000196:embryology* / Q000503:physiopathology; D001921:Brain / Q000002:abnormalities / Q000098:blood supply / Q000196:embryology / Q000473:pathology; D020964:Embryo Loss; D042783:Endothelial Cells / Q000378:metabolism; D018390:Gene Targeting; D006470:Hemorrhage / Q000196:embryology / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006579:Heterozygote; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D011486:Protein C / Q000378:metabolism; D017293:Protein S / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018455:Protein S Deficiency / Q000196:embryology* / Q000473:pathology / Q000503:physiopathology*; D013116:Spinal Cord / Q000098:blood supply / Q000196:embryology; D013917:Thrombin / Q000378:metabolism
chemical_list: D011486:Protein C; D017293:Protein S; D013917:Thrombin