The Controversial Role of the Urokinase System in Abdominal Aortic Aneurysm Formation and Rupture

Abstract

In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Uchida et al report the use of a urokinase plasminogen activator (uPA)−/− low-density lipoprotein receptor−/− mouse model to investigate the role of uPA in the development of abdominal aortic aneurysm (AAA) in a hyperlipidemic setting.1 Surprisingly, they show that uPA deficiency has a detrimental role in the rupture of AAA, but not a role in AAA formation. AAA results from progressive degeneration of the aortic wall due to degradation of key extracellular matrix proteins, namely collagen and elastin. This leads to gradual weakening and instability of the vessel wall, dilatation of the vessel, and eventual rupture. Rupture is life threatening, accounting for approximately 15 000 deaths per year in the United States. Although recent progress has been made in detection and repair of AAA, few molecular mechanisms have been elucidated in the pathogenesis of AAA, including those related to inflammation, infection, protease activation, and underlying genetic mutations. Several families of proteinases are implicated in AAA development, including aspartic, serine, and metalloproteinases. Particularly, the matrix metalloproteinase family has been extensively studied and linked to AAA formation and expansion.2 Recently, the focus has shifted to serine proteinases involved in fibrinolysis, namely tissue plasminogen activator (tPA) and uPA, as potential mediators of inflammation and proteolysis in AAA (Figure). uPA and tPA cleave plasminogen to plasmin, which can in turn activate matrix metalloproteinases, potentially increasing the proteolytic activity of nearby cells. However, the exact mechanisms linking the uPA/urokinase receptor (uPAR) system to AAA have yet to be fully identified. Figure. Top: Presumed role of the fibrinolytic system to activate plasminogen to plasmin for increased proteolytic activity during AAA formation. Bottom: The contrasting results …