Abstract 19163: Rapid Progressive Thoracic and Abdominal Aneurysm Model in Fbn1C1039G/+ Mice Treated With Angiotensin Ii

Abstract

Rationale: Marfan syndrome patients typically develop aortic root aneurysms with ensuing aortic dissection remaining the leading cause of death. Although losartan (Angiotensin 1 receptor blocker) has been shown to reduce aneurysms in mice, the role Angiotensin II (AngII) plays during aneurysm formation in MFS remains unknown. Objective: We hypothesized that AngII may exacerbate aneurysm growth in Fbn1 C1039G/+ mice. Moreover, we predicted AngII would induce abdominal aneurysms, creating a novel model to study the pathophysiology of aneurysm formation with two different embryonic origins. Method and results: Fbn1 C1039G/+ mice (n = 7) were treated with either (a) AngII (500 ng/min/kg) or (b) vehicle control and compared to ApoE-/- mice treated with Ang II (1000 ng/min/kg). Aortic root, ascending and abdominal diameters are measured with echo on POD 3, 7 and 14. Following dose-response curve experiments, optimal survival rate is 70%, 14 days after treatment. The average aortic root/ascending (AS) aortic diameter in Ang II Fbn1 C1039G/+ mice was 2.08 ± 0.31 mm, compared to 1.48 ± 0.25 mm in vehicle control Fbn1 C1039G/+ mice (p<.05). Interestingly, in addition to AS aortic aneurysms, 50% developed abdominal aneurysms. Cause of death in Ang II Fbn1 C1039G/+ mice were due to either AS or abdominal aneurysm dissection. Immunohistochemistry on POD 14 showed severe elastic layer disruption in aneurysmal tissue from both aneurysms. Quantitative PCR was performed to measure the expression of matrix-metalloproteinase (MMP) gene expression. When comparing AS and abdominal aneurysms in AngII Fbn1 C1039G/+ mice, MMP-2 was highly up-regulated in AS aneurysms (Fold change: 3.03 ± 0.69, p<0.05), whereas MMP-9 was up-regulated in abdominal aneurysms (Fold change: 1.86 ± 0.15, p<0.05). In contrast, MMP-9 was down-regulated in abdominal aneurysms in AngII ApoE-/- mice (Fold change: 0.18 ± 0.13, p<0.05). Conclusions: Fbn1 C1039G/+ mice treated with AngII develop severe aortic root/ascending aortic aneurysms. Ang II treatment results in abdominal aneurysm formation. Interestingly, gene expression analyses suggest different mechanisms of aneurysm development in aortic segments of different embryonic origin.