Based on the large amounts of atherosclerotic plaque in AAA operative specimens, it was initially thought that AAA is the product of atherosclerotic degeneration. Furthermore, both AAAs and atherosclerotic plaques tend to localize to the infrarenal aorta, and the two diseases share various risk factors, such as smoking, hypertension, and hypercholesterolemia. However, despite this strong association, there are other features of aneurysmal and occlusive disease, which suggest distinct etiologies. Specifically, aneurysms occur in an older population with a greater degree of male gender specificity. Furthermore, they are uncommonly associated with significant occlusive disease and tend to affect the proximal to mid-infrarenal aorta, rather than follow the aortic bifurcation and femoropopliteal distribution of atherosclerosis. Additionally, animals on atherogenic diets may develop severe atherosclerosis but very rarely develop aneurysmal disease. Specifically, in two separate reports of squirrel monkeys that were fed an atherogenic diet for 9 to 79 months, severe atherosclerosis developed in all, but aneurysms developed in only 1.5%. A third study reported a 10% incidence of aneurysms in cynomolgus monkeys fed an atherogenic diet. The authors noted that aneurysm formation increased when animals were placed on a regression diet with cholestyramine after a period of hypercholesterolemia and suggested that atherosclerotic plaque regression could play a role in aneurysm formation. Of note, these experimental aneurysms tended to be diverse in location and favored the thoracic aorta, in contrast to human aortic aneurysmal disease. These data indicate that although atherosclerosis is probably a permissive factor required for aneurysm development, other factors must also be important.

The tensile strength and elasticity of the aortic wall are largely conferred by its most important structural elements, the matrix proteins collagen and elastin. These two proteins are synthesized and maintained by the resident mesenchymal cells and with them are organized into highly regulated lamellar units designed to maintain the functional integrity of the vascular wall. The mesenchymal cells include smooth muscle cells in the arterial media and fibroblasts in the adventitia. Collagen is a component of both the normal lamellar structure of the aortic media and the surrounding fibrous adventitia. The fiber-forming collagens, especially types I and III, are the predominant types in the aorta. Together, these collagens primarily impart tensile strength, but they also contribute to the extensile properties of the aorta. Elastin, the other important component of the vascular wall matrix, is responsible for the viscous and elastic properties of the aorta. It is composed of cross-linked tropoelastin monomers arranged on a scaffold of microfibrillar proteins. By forming stable cross-links, these fibers become highly resistant to proteolytic degradation and have a half-life measured in decades.

Histologic evaluation of AAAs demonstrates advanced degeneration of all components of the normal lamellar structure. Specifically, there is extensive lamellar disruption with destruction of elastin and collagen in both media and adventitia. Despite the advanced degeneration of elastin and collagen in both media and adventitia, their precursory molecules, especially the procollagens, are abundantly expressed in AAAs. Additionally, AAAs have been noted to have ninefold lower levels of desmosine, a marker of mature, cross-linked elastin, and a fourfold to sixfold increase in levels of tropoelastin as compared with normal aortas. These findings suggest ongoing, but ineffective, collagenogenesis and elastogenesis by the aortic mesenchymal cells. This impairment in the integration of new collagen and elastin fibers may severely compromise the integrity and biomechanical properties of the arterial wall, rendering these components more susceptible to further enzymatic degradation.

The changes in elastin and collagen content and architecture noted in aneurysm tissue appear to play a central role in pathogenesis of aortic aneurysms. Early studies demonstrated that enzymatic treatment of arteries with elastase leads to arterial dilation without rupture, while treatment with collagenase leads to arterial rupture with little dilation. Compelling evidence indicates that AAAs are associated with increased local production of proteinases capable of degrading both collagen and elastin. These enzymes, known as matrix metalloproteinases (MMPs), are zinc-endopeptidases that can degrade all components of extracellular matrix. Enzymes that can degrade elastin include the 92-kd gelatinase (MMP-9), 72-kd gelatinase (MMP-2), matrilysin (MMP-8), macrophage metalloelastase (MMP-12), the serine protease, and neutrophil elastase. Enzymes that can degrade type IV collagen include MMP-9 and MMP-12, while MMP-1, MMP-2, MMP-8, and MMP-13 have been shown to have true collagenolytic activity.

AAAs have increased elastolytic activity, and smooth muscle cells from AAA explants secrete increased amounts of proteolytic enzymes in response to stimulation by elastin degradation products. Several of the MMPs have been identified in AAA tissue, including MMP-1, MMP-2, MMP-3, MMP-9, and MMP-12. In comparison to homogenates from normal aortic tissue, AAA tissue homogenates have demonstrated increased MMP-9 activity. Additionally, explant cultures of AAA tissue produce more MMP-9 than either normal or aortic occlusive disease controls. This conclusion was further supported by immunohistochemical tissue analysis. Because of the prominence of MMP-9 in both aortic occlusive disease and AAA, a number of studies have addressed the cellular source of this protease. Macrophages are believed to be the primary source of MMP-9 in AAAs, but good evidence is available to suggest that smooth muscle cells may also be a source for this enzyme. The normal aorta appears to express MMP-9 in the absence of invading inflammatory cells, and smooth muscle cells derived from AAA secrete MMP-9 in culture. In addition, cultured aneurysmal smooth muscle cells demonstrate an increased expression of metalloproteinases in response to pro-inflammatory cytokines. Because the smooth muscle cell phenotype may change dramatically under culture conditions, these studies should be interpreted with some caution.

Although much attention has been focused on the role of MMP-9 in aneurysm pathogenesis, recent work suggests that MMP-2 may have a greater potential to regulate matrix degradation than other proteinases. MMP-2 is the only proteinase capable of degrading not just elastin but also intact fibrous collagen. It has been shown that degradation of the fibrous collagen of the adventitia is essential for the development of AAA. Furthermore, the primary source of MMP-2 is the same mesenchymal cells that produce elastin and collagen. Those cells are smooth muscle cells in the arterial media and fibroblasts in the adventitia. Moreover, MMP-2 is a more potent elastase than MMP-9. Like those of MMP-9, tissue levels of MMP-2 appear to be increased in aorta in both AAA and athero-occlusive disease, in comparison to normal controls. Specifically, an increase in MMP-2 and MMP-2 mRNA was found in aneurysms in comparison with aortic occlusive disease and normal controls. Like other MMPs, MMP-2 is secreted as a latent proenzyme (72 kd) that must be cleaved to its active, 62-kd form. Compared to normal aortas and aortas with athero-occlusive disease, a far greater proportion of the AAA MMP-2 is in the active 62-kd form and tightly bound to its matrix substrate, and these findings lend additional support for a direct role in matrix destruction. Some MMPs are activated by serine proteinases, but MMP-2 cannot be activated by this pathway. MMP-2 is uniquely activated on the cell surface by a newly recognized family of membrane-bound or membrane-type (MT) MMPs. Five different MT-MMPs have been identified and are designated MT1-MMP through MT5-MMP. All were identified by homology screening of cDNA libraries and placed in the MT-MMP family because of their putative transmembrane domains. They form a distinct subclass (MT subclass) of the MMP family, as all other MMPs are secreted in a soluble form. In this subclass, only MT1-MMP has been well characterized. MT1-MMP appears to play a central role in MMP-2 activation in vascular smooth muscle cells. Tissue inhibitor of metalloproteinases (TIMP-2) has been found to be a cofactor required for MT1-MMP activation of MMP-2 at precise, relatively low molar concentrations.

The most convincing data to date indicating that MMPs cause AAAs were recently reported in a study of a rat aneurysm model. The model involves xenotransplantation model of an acellular guinea pig aorta into a rat infrarenal aorta. This model mimics human AAA in the up-regulation of MMP-9 and activation of MMP-2. In this study the luminal side of the transplanted aortas was coated with rat smooth muscle cells retrovirally transfected with the TIMP-1 gene. TIMP-1 overexpression blocked the activation of both MMP-9 and MMP-2 and therefore inhibited aneurysm formation. The exact mechanism of inhibition of MMP-2 activation is not clear because high local concentrations of TIMP-2 (not TIMP-1) are required to block MT1-MMP activation of MMP-2. Therefore, these studies suggest a possible role for MMP-9 and MMP-2 in the early development of AAA.