Combining two potential causes of metalloproteinase secretion causes abdominal aortic aneurysms in rats: a new experimental model

Abstract

Progress in understanding the pathophysiology of abdominal aortic aneurysms (AAA) is dependent in part on the development and application of effective animal models that recapitulate key aspects of the disease. The objective was to produce an experimental model of AAA in rats by combining two potential causes of metalloproteinase (MMP) secretion: inflammation and turbulent blood flow. Male Wistar rats were randomly divided in four groups: Injury, Stenosis, Aneurysm and Control (40/group). The Injury group received a traumatic injury to the external aortic wall. The Stenosis group received an extrinsic stenosis at a corresponding location. The Aneurysm group received both the injury and stenosis simultaneously, and the Control group received a sham operation. Animals were euthanized at days 1, 3, 7 and 15. Aorta and/or aneurysms were collected and the fragments were fixed for morphologic, immunohistochemistry and morphometric analyses or frozen for MMP assays. AAAs had developed by day 3 in 60-70% of the animals, reaching an aortic dilatation ratio of more than 300%, exhibiting intense wall remodelling initiated at the adventitia and characterized by an obvious inflammatory infiltrate, mesenchymal proliferation, neoangiogenesis, elastin degradation and collagen deposition. Immunohistochemistry and zymography studies displayed significantly increased expressions of MMP-2 and MMP-9 in aneurysm walls compared to other groups. The haemo-dynamic alterations caused by the stenosis may have provided additional contribution to the MMPs liberation. This new model illustrated that AAA can be multifactorial and confirmed the key roles of MMP-2 and MMP-9 in this dynamic remodelling process.

miR-29b Participates in Early Aneurysm Development in Marfan Syndrome

“…Several investigators have reported that enhanced MMP production promotes abdominal aneurysm formation by increasing ECM destruction. 16,17 In this study, both MMP-2 expression and activity were specifically upregulated in the AS segment of the Marfan aorta only, explaining the disruption of medial wall ELN isolated to this area. MMPs are secreted by leukocytes and SMCs, 27,28 and MMP-2 can degrade both elastin and collagen.…”

“…Furthermore, the reduced ELN mRNA in the AS aorta of the Fbn1 Proteolytic degradation of ELN within the aortic wall media by MMPs participates in aneurysm development. 16,17 The increased fragmentation of ELN evident on histological examination of the AS segments from Fbn1 C1039G/ϩ mice suggest that heightened proteolytic activity may be an additional mechanism explaining the aneurysm formation in the AS aorta of these mice. Quantitative polymerase chain reaction analysis revealed Ͼ3-fold increase in MMP-2 at 2 weeks in the Fbn1 C1039G/ϩ AS aorta as compared to WT AS aorta (3.28Ϯ0.50-fold increase compared to WT; Pϭ0.027), and a similar increase as compared to MMP-2 levels at 8 weeks (3.71Ϯ0.86-fold increase; Pϭ0.021; Figure 3C).…”

Coronary Artery Aneurysms: An Update

“…Unfortunately, the lack of specific prodromal symptoms or factors predisposing to the formation of CAAs significantly limits the diagnostic possibilities, and consequently, the therapeutic modalities. One way to improve the understanding of the pathogenesis of aneurysms can be through the development of experimental models, such as those that are used for studying abdominal aortic aneurysms (Mata et al, 2011). Thus, this review aimed to provide an update on the pathogenesis and treatment of CAAs to highlight for physicians and thoracic surgeons the practical management of patients with this disease and to help avoid major complications, such as death.…”

“…The pathophysiology is focal destruction of the internal elastic lamina with early neutrophil infiltration followed by macrophages and cytotoxic T lymphocytes (Takahashi et al, 2005). Increased proteolysis of extracellular matrix proteins is probably a mechanism of CAA formation (Mata et al, 2011). MMPs (1, 2, 3, 9 and 12) are capable of degrading essentially all components of the arterial wall matrix (elastin, collagen, proteoglycans, laminin, fibronectin, etc.…”

The Role of Metalloproteinases in the Development of Aneurysm

“…Exposure of the arterial wall to an increased concentration of angiotensin II represents conditions that may be observed in patients with arterial hypertension. This experiment demonstrates that coexistance of arterial hypertension and smoking augments the risk of a development of aneurysm [14,15].…”