Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity.

Area of Science:

• Vascular Biology
• Lipidomics
• Hemostasis and Thrombosis

Background:

• Abdominal aortic aneurysm (AAA) is a life-threatening inflammatory vascular disease with limited treatment options.
• The role of blood lipids, particularly oxidized phospholipids, in AAA pathogenesis remains largely unknown.
• Understanding lipid regulation of AAA is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To investigate the role of procoagulant enzymatically oxidized phospholipids (eoxPL) in abdominal aortic aneurysm (AAA) development.
• To elucidate the mechanisms by which eoxPL influence coagulation and AAA progression.
• To identify specific eoxPL molecular species involved in AAA pathogenesis.

Main Methods:

• Lipidomics analysis of AAA lesions in mouse models and human samples.
• Genetic manipulation of eoxPL-generating enzymes (Alox12, Alox15) in mice.
• Pharmacological inhibition of coagulation factor Xa using rivaroxaban.
• Assessment of hemostatic balance, including clotting factor activation and consumption.

Main Results:

• Elevated levels of eoxPL were detected in both mouse and human AAA lesions.
• Deletion of eoxPL-generating enzymes or inhibition of factor Xa significantly reduced AAA development.
• Intravenously administered procoagulant phospholipids induced clotting factor depletion and reduced AAA.
• Alox-deficient mice exhibited dysregulated hemostasis with compensatory increases in prothrombotic phospholipids.

Conclusions:

• Procoagulant eoxPL are critical regulators of AAA development, influencing coagulation dynamics.
• The localization of eoxPL (intravascular vs. vessel wall) determines their pro- or anti-aneurysmal effects.
• Targeting the balance between bleeding and thrombosis by modulating eoxPL offers a potential therapeutic approach for AAA.