Regulation of fibrinolysis by S100A10 in vivo

Alexi P Surette, Patricia A Madureira, Kyle D Phipps, Victoria A Miller, Per Svenningsson, David M Waisman

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3172-3181
Number of pages10
JournalBlood
Volume118
Issue number11
DOIs
Publication statusPublished - 15 Sep 2011

Keywords

  • Animals
  • Annexin A2/genetics
  • Cells, Cultured
  • Endothelial Cells/metabolism
  • Female
  • Fibrin/metabolism
  • Fibrinolysin/metabolism
  • Fibrinolysis/genetics
  • Hemorrhage/genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Physiologic/genetics
  • S100 Proteins/genetics

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