Expression of fibrinolytic genes in atherosclerotic abdominal aortic aneurysm wall. A possible mechanism for aneurysm expansion.

Abstract

Expansion of atherosclerotic abdominal aortic aneurysm (AAA) has been attributed to remodeling of the extracellular matrix by active proteolysis. We used in situ hybridization to analyze the expression of fibrinolytic genes in aneurysm wall from eight AAA patients. All specimens exhibited specific areas of inflammatory infiltrates with macrophagelike cells expressing urokinase-type plasminogen activator (u-PA) and tissue-type PA (t-PA) mRNA. Type 1 PA inhibitor (PAM-) mRNA was expressed at the base of the necrotic atheroma of all specimens and also within some of the inflammatory infiltrates where it frequently colocalized in regions contining u-PA and t-PA mRNA expressing cells.However, in these areas, the cellular distribution of the transcripts for t-PA and u-PA extended far beyond the areas of PAT-i expression. These observations suggest a local ongoing proteolytic process, one which is only partially counteracted by the more restricted expression of PAT-i mRNA. An abundance of capillaries was also obvious in all inflammatory infiltrates and may reflect local angiogenesis in response to active pericellular fibrinolysis. The increased fibrinolytic capacity in AAA wall may promote angiogenesis and contribute to local proteolytic degradation of the aortic wall leading to physical weakening and active expansion of the aneurysm. (J. Clin. Invest. 1995. 96:639-645.)

Angiotensin II Increases Urokinase-Type Plasminogen Activator Expression and Induces Aneurysm in the Abdominal Aorta of Apolipoprotein E-Deficient Mice

“…The features are commonly seen in human AAAs. 1,5,15 In addition, Ang II accelerated atherosclerosis and resulted in a modest increase in blood pressure.…”

“…1,2,4,17 Many pro-MMPs are activated by plasmin which, in turn, is activated by uPA. uPA expression was increased 13-fold in the aneurysmal segment of Ang II-treated apoE-KO mice compared to vehicletreated controls.…”

“…Biochemical studies have demonstrated increased proteolytic activity in the aortic wall of AAA. Schneiderman and colleagues 1 showed that uPA mRNA as well as the tissue-type plasminogen activator (tPA), co-localized with infiltrating macrophages, is significantly increased in human AAA. Increased activities of MMP-2, -3, -9, and -12 in AAA have also been reported.…”

Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice

“…23 This is consistent with other observations that human aneurysm lesions have increased tPA and uPA gene expression which could result in enhanced fibrinolytic and proteolytic activity in the AAA wall. 24 In a series of experiments, we tested the hypothesis that inhibition of uPA by overexpression of human PAI-1 prevents the development and progression of AAA. The PAI-1 gene was delivered locally to the vascular wall by injecting adenoviral human PAI-1 (Ad5.CMV.PAI-1) directly into the perivascular layer of the abdominal aorta.…”

Natriuretic Factors and Nitric Oxide Suppress Plasminogen Activator Inhibitor-1 Expression in Vascular Smooth Muscle Cells

“…Conversely, a local increase in plasminogen activation potential within the vascular wall, associated with a relative increase in tissue plasminogen activator and urokinase plasminogen activator expression compared with that of PAI-1, has been shown at sites of abdominal aortic aneurysms. 20,21 Within these sites, high levels of plasmin may locally increase proteolysis of ECM and thereby physically weaken the vascular wall.…”