title: Regulation of fibrinolysis by S100A10 in vivo.
abstract: Endothelial cells form the inner lining of vascular networks and maintain blood fluidity by inhibiting blood coagulation and promoting blood clot dissolution (fibrinolysis). Plasmin, the primary fibrinolytic enzyme, is generated by the cleavage of the plasma protein, plasminogen, by its activator, tissue plasminogen activator. This reaction is regulated by plasminogen receptors at the surface of the vascular endothelial cells. Previous studies have identified the plasminogen receptor protein S100A10 as a key regulator of plasmin generation by cancer cells and macrophages. Here we examine the role of S100A10 and its annexin A2 binding partner in endothelial cell function using a homozygous S100A10-null mouse. Compared with wild-type mice, S100A10-null mice displayed increased deposition of fibrin in the vasculature and reduced clearance of batroxobin-induced vascular thrombi, suggesting a role for S100A10 in fibrinolysis in vivo. Compared with wild-type cells, endothelial cells from S100A10-null mice demonstrated a 40% reduction in plasminogen binding and plasmin generation in vitro. Furthermore, S100A10-deficient endothelial cells demonstrated impaired neovascularization of Matrigel plugs in vivo, suggesting a role for S100A10 in angiogenesis. These results establish an important role for S100A10 in the regulation of fibrinolysis and angiogenesis in vivo, suggesting S100A10 plays a critical role in endothelial cell function.
authors.affiliation: Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS.
authors.forename: Alexi P
authors.initials: AP
authors.lastname: Surette
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Madureira
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Phipps
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Miller
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.forename: David M
authors.initials: DM
authors.lastname: Waisman
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis / Q000235:genetics*; D006470:Hemorrhage / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D005337:Fibrin; D005341:Fibrinolysin; D009418:S100 Proteins; D000099248:S100 Calcium Binding Protein A10