Angiotensin II increases urokinase-type plasminogen activator expression and induces aneurysm in the abdominal aorta of apolipoprotein E-deficient mice

Urokinase-type plasminogen activator (uPA) is increased in human abdominal aortic aneurysm (AAA). Chronic infusion of angiotensin H (Ang II) results i n ANA in apolipoprotein E-deficient Mice. We tested the hypothesis that Ang II infusion results in an elevation of uPA expression contributing to aneu rysm formation. Ang II or vehicle was infused by osmotic pumps into apoE-KO mice. All mice treated with Ang H developed a localized expansion of the s uprarenal aorta (75% increase in outer diameter), accompanied by an elevati on of blood pressure (22 mmHg), compared to the vehicle-treated group. Hist ological examination of the dilated aortic segment revealed similarities to human AAA including focal elastin fragmentation, macrophage infiltration, and intravascular hemorrhage. Ang H treatment resulted in a 13-fold increas e in the expression of uPA mRNA in the AAA segment in contrast to a twofold increase in the atherosclerotic aortic arch. Increased uPA protein was det ected in the abdominal aorta as early as 10 days after Ang II infusion befo re significant aorta expansion. Thus, Ang H infusion results in macrophage infiltration, increased uPA activity, and aneurysm formation in the abdomin al aorta of apoE-KO mice. These data are consistent with a causal role for uPA in the pathogenesis of AAA.