Mesoglycan exerts its fibrinolytic effect through the activation of annexin A2

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Mesoglycan, a glycosaminoglycan mixture, is used for blood vessel diseases as an antithrombotic and profibrinolytic agent.
• The precise mechanism of mesoglycan's action on the fibrinolytic cascade, particularly its effect on endothelial cells, remains unclear.

Purpose of the Study:

• To elucidate the mechanism by which mesoglycan induces plasmin activation from endothelial cells.
• To investigate the role of annexin A2 (ANXA2) and syndecan 4 (SDC4) in mesoglycan's profibrinolytic activity.

Main Methods:

• Proteomic analysis to identify proteins translocated to the plasma membrane after mesoglycan treatment.
• Cellular assays to evaluate the impact of mesoglycan on cell migration, invasion, angiogenesis, and plasmin release.
• Investigation of signaling pathways, including src complex and PKCα, involved in ANXA2 phosphorylation and translocation.

Main Results:

• Mesoglycan treatment led to the translocation of annexin A2 (ANXA2) to the plasma membrane of endothelial cells, enhancing cell migration, invasion, and angiogenesis.
• The interaction between mesoglycan and syndecan 4 (SDC4) was identified as an upstream event triggering endothelial cell motility and angiogenesis.
• Mesoglycan induced plasmin release from endothelial cell supernatants specifically in the presence of ANXA2, indicating its crucial role in the cascade.

Conclusions:

• Mesoglycan initiates a signaling cascade involving SDC4 activation, src complex and PKCα, leading to ANXA2 phosphorylation and membrane translocation.
• This mechanism facilitates the proximity of plasminogen to tissue plasminogen activator, promoting plasmin generation and subsequent fibrin degradation.
• The study reveals a novel connection between mesoglycan, SDC4, ANXA2, and the fibrinolytic system, clarifying mesoglycan's profibrinolytic action.