Hemostasis and endothelial functionality: the double face of coagulation factors

Abstract

Hemostasis is a sophisticated sequence of events aimed at repairing vessel injury. This process occurs in combination with angiogenesis, which leads to new blood vessel formation, helping in wound repair and facilitating tissue healing. The fine mechanisms that regulate hemostasis and angiogenesis are well described, but for a long time, coagulation factors (CF) have been considered merely players in the coagulation cascade. However, evidence from several experiments highlights the crucial functions of these CF in regulating endothelial functionality, especially in the angiogenic process. Some of these CF (e.g., thrombin and tissue factor) have been widely investigated and have been described as triggering intracellular signaling related to endothelial cell (EC) functionality. For others (e.g., factor VIII and thrombomodulin), potential receptors and molecular mechanisms have not been fully elucidated but some data show their potential to induce EC response. This review focuses on the emerging roles of selected CF in regulating EC functions, highlighting in particular their ability to activate signaling pathways involved in angiogenesis, migration, proliferation and endothelial barrier stability.

Figure 1.

Coagulation factors binding to receptors involved in endothelial cell functions. Antithrombin binds to heparan sulfate proteoglycans (HSPG) to exert its function in endothelial cells (EC). Thrombomodulin can induce the expression of genes involved in extracellular matrix and angiogenesis. Thrombin and tissue factor bind G-protein coupled receptors and integrins. von Wille-brand factor (vWF) binds integrin on EC and activated protein C (APC) binds G-protein coupled receptors and receptor tyrosine kinases (RTK). Factor VIII (FVIII) binds to known scavenger receptors, but its involvement with integrins or RTK in the regulation of EC functionality has never been fully explored. The activation of these receptors induces the expression of genes involved in extracellular matrix organization and angiogenesis modulating EC functions.