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 (tPA). 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 to 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 to WT 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.

Thesis--Copenhagen. / Bibliography: p. [65]-73.

Thesis--Copenhagen. / Bibliography: p. [65]-73.

Thesis (doctoral)--University of Lund.

No description available.

No description available.

A number of questions about the hepatic mechanisms of tissue-type plasminogen activator (t-PA) clearance still remain unanswered. Although certain liver endothelial cell receptors have been implicated, the parenchymal cell system, which is responsible for most clearance, still remains a mystery. The aim of this project, in the most simple terms, was to solve this mystery. The foundation upon which this project was built was that t-PA is cleared, by a hepatic receptor, in complex with its primary inhibitor, plasminogen activator inhibitor type 1 (PAI-1). The affinity of binding was estimated to be 0.8-1.0 nM and the number of binding sites per cell, 35 000-70 000. Affinity chromatography and chemical cross-linking resulted in a band of A?70 kDa which was presumed to be the receptor. This project was designed to characterize this hepatic receptor for t-PA-PAI-1 and determine whether plasmin-2-antiplasmin (PAP) is recognised by the same receptor. Characterizing the receptor was attempted initially by employing cell binding assays using the human hepatoma cell line, Hep G2. This methodology required the formation and characterization of pure pre-formed ligands which was achieved by overcoming preliminary problems. The binding assays showed that competition between t-PA-PAI-1 and PAP was occurring but that high non-specific binding and error between duplicate samples suggested that this system was not suitable for characterization of the receptor. The data accumulated in this study suggested that LRP was primarily responsible for hepatic uptake of t-PA and that proteases were recognised preferentially in complex with their inhibitors.

Diss. (sammanfattning) Göteborg : Univ. , 2007. / Härtill 5 uppsatser.

Thesis (Ph.D.)--Drexel University, 2008. / Includes abstract. Includes bibliographical references (leaves 76-83).

Thesis (Ph.D.)--Aberdeen University, 2009. / Title from web page (viewed on June 11, 2009). Includes bibliographical references.