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Hemodynamics and pathology of an enlarging abdominal aortic aneurysm model in rabbits.

ABSTRACT: Hemodynamics may play an essential role in the initiation and progression of abdominal aortic aneurysm (AAA). We aimed to study the mechanism of self-healing process by the changes of hemodynamics and pathology in an enlarging AAA in rabbits. Seventy-two rabbits were randomly divided into three groups. Rabbits underwent extrinsic coarctation and received a 10-minute elastase incubation in Group A and Group B. Absorbable suture used in Group A was terminated by balloon dilation at week 4. Diameter was measured after 1, 3, 5, and 15 weeks, computational fluid dynamics analysis was performed at week 3 and week 15. Rabbits were sacrificed after 1, 5, and 15 weeks for pathological and quantitative studies. The higher velocity magnitude, intensified bulk flow and obvious vortex formation were observed in Group A at week 3 instead of week 15. Both low wall shear stress and high relative residence time increased in Group B, however, high oscillatory shear index had relatively less increase compared with Group A. Aortic diameter reached a plateau at 5 weeks in Group A, which was significantly lower than in week 15 in Group B. Intimal hyperplasia, intima-media thickness increased significantly in Group A at week 5, significantly higher than in week 15 in Group B. Marked destruction of elastin fibers and smooth muscle cells occurred at week 1, and increased significantly at week 15 in Group A. Aneurysm exhibited strong expression of matrix metalloproteinase 9 and mouse anti-rabbit macrophage 11 at week 1, and showed a tendency to decrease. Matrix metalloproteinase 2 expression decreased significantly in Group B at week 15 compared with week 5 and Group A. In conclusion, the self-healing of rabbit AAA may attributed to the regeneration of smooth muscle cells. The turbulence flow caused by coarctation is associated with continuous growth of rabbit AAA and prevents the self-healing phenomenon.

SUBMITTER: Chen H

PROVIDER: S-EPMC6185729 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Hemodynamics and pathology of an enlarging abdominal aortic aneurysm model in rabbits.

Chen Hongmei H Bi Yonghua Y Ju Siyeong S Gu Linxia L Zhu Xiaoyan X Han Xinwei X

PloS one 20181012 10

Hemodynamics may play an essential role in the initiation and progression of abdominal aortic aneurysm (AAA). We aimed to study the mechanism of self-healing process by the changes of hemodynamics and pathology in an enlarging AAA in rabbits. Seventy-two rabbits were randomly divided into three groups. Rabbits underwent extrinsic coarctation and received a 10-minute elastase incubation in Group A and Group B. Absorbable suture used in Group A was terminated by balloon dilation at week 4. Diamete ...[more]

PMID: 30312321

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Project description:The self-healing phenomenon can be found in the elastase-induced abdominal aortic aneurysm (AAA) model, and an enlarging AAA model was successfully induced by coarctation. Unfortunately, aortic coarctation in these enlarging models is generally not found in human AAA disease. This study aimed to create an experiment model of enlarging AAA in rabbits to better mimic human aortic aneurysm disease. Eighty-four male New Zealand white rabbits were randomly divided into three equal groups: two aneurysm groups (A and B) and a SHAM group. Aneurysm group rabbits underwent extrinsic aortic stenosis below the right renal artery and received a 10-minute incubation of 60 μl elastase (1 unit/μl). Absorbable suture was used in Group A and nonabsorbable cotton thread was used in Group B. A sham operation was performed in the SHAM group. Aortic diameter was measured after 1, 3, 7, and 15 weeks; thereafter animals were sacrificed for histopathological, immunohistochemical and quantitative studies. Two rabbits died at 29 and 48 days, respectively, after operation in Group B. All aneurysms formed and enlarged progressively by 3 weeks in the Aneurysm groups. However, diameter enlargement in Group A was significantly lower than that in Group B at 7 weeks. Aneurysm groups developed intimal hyperplasia; intima-media thickness (IMT) increased significantly by week 7, and aortic media thickness and intima-media ratio (IMR) increased significantly by week 15. Marked destruction of elastin fibers and smooth muscle cells (SMCs) occurred 1 week later and increased progressively thereafter. Intimal hyperplasia and SMCs content in Group A increased significantly by week 15 compared with Group B. Aneurysm groups exhibited strong expression of matrix metalloproteinases 2 and 9 and RAM11 by week 1, and decreased progressively thereafter. In conclusion, this novel rabbit AAA model enlarges progressively without coarctation and is capable of better mimicking human aortic aneurysm disease.

Project description:ObjectiveFew large-animal models exist for the study of aortic aneurysms. β-Aminopropionitrile (BAPN) is a compound known to cause aortic aneurysms by inhibiting lysyl oxidase, a collagen cross-linking enzyme. It is hypothesized that BAPN plus aneurysm induction surgery would result in significant aneurysm formation in swine with biologic properties similar to human disease.MethodsInitial experiments were performed in uncastrated male swine not treated with BAPN (surgery alone). Subsequently, uncastrated male swine were fed BAPN (0.15 g/kg) for 7 days before undergoing surgery; the infrarenal aorta was circumferentially dissected and measured, balloon dilated, and perfused with elastase (500 units) and type I collagenase (8000 units), with extraluminal elastase application. In the BAPN groups, daily BAPN feedings continued until swine harvest at postoperative days 7, 14, and 28.ResultsSwine undergoing surgery alone (n = 12) had significantly less dilation at 28 days compared with BAPN + surgery swine (51.9% ± 29.2% [0%-100%] vs 113.5% ± 30.2% [52.9%-146.2%]; P < .0003). Mean aortic dilation in animals undergoing treatment with surgery and BAPN was 86.9% ± 47.4% (range, 55.6%-157.1%), 105.4% ± 58.1% (50%-133.3%), and 113.5% ± 30.2% (52.9%-146.2%) at 7, 14, and 28 days, respectively. In the BAPN + surgery group, significant elastolysis was present at all time points, whereas aortic wall collagen content was not significantly different. Smooth muscle cells were significantly depleted at 14 and 28 days, and M1 macrophages were increased at 14 and 28 days (P < .05, all). Matrix metalloproteinase 2 was elevated at 7 days (P < .05). Multiple proinflammatory cytokines were elevated within the aortic wall of BAPN + surgery swine.ConclusionsBAPN plus surgery resulted in significantly larger aortic aneurysms than surgery alone and was critical to aneurysm formation in this novel swine model. Hallmarks of human disease, such as elastin fragmentation, smooth muscle cell depletion, macrophage infiltration, matrix metalloproteinase activation, and proinflammatory cytokine expression, were observed in BAPN-treated swine. This model better parallels many of the characteristics of human AAAs and may be suitable for prehuman drug trials.

Project description:The purpose of this study was to establish a reliable, chronic model of abdominal aortic aneurysm (AAA).Wild-type 8-week-old C56BL/6 male mice (n = 120) were equally divided into three groups: (1) BAPN group: 0.2% 3-aminopropionitrile fumarate salt (BAPN) drinking water was provided to mice 2 days before surgery until the end of study. Sham aneurysm induction surgery was performed using 5 ?L of heat deactivated elastase. (2) Elastase group: mice were given regular drinking water without BAPN. During aneurysm induction surgery, 5 ?L of the active form of elastase (10.3 mg protein/mL, 5.9 U/mg protein) was applied on top of the infrarenal abdominal aorta adventitia for 5 minutes. (3) BAPN+elastase group: mice were given BAPN drinking water and the active form of elastase application, as above. On postoperative days 7, 14, 21, 28, and 100, aortic samples were collected for histology, cytokine array, and gelatin zymography after aortic diameter measurement.Compared with the elastase group, the BAPN+elastase group had a higher AAA formation rate (93% vs 65%; P < .01) with more advanced AAAs (25 of 42 vs 1 of 40 for stage II and III; P < .001). Aneurysms from the BAPN+elastase group demonstrated persistent long-term growth (221.5% ± 36.6%, 285.8% ± 78.6%, and 801% ± 160% on days 21, 28, and 100, respectively; P < .001), with considerable thrombus formation (54%) and rupture (31%) at the advanced stages of AAA development. Cytokine levels (pro-matrix metalloproteinase 9, interleukin-1?, interleukin-6, chemokine [C-C motif] ligand 5, triggering receptor expressed on myeloid cells 1, monocyte chemotactic protein 1, and tissue inhibitor of metalloproteinase 1) in the BAPN+elastase group were higher than in the elastase group on day 7. After day 7, cytokine levels returned to baseline, with the exception of elevated matrix metalloproteinase 2 activity. By histology, CD3-positive T cells in the BAPN+elastase group were elevated on days 28 and 100.A combination of oral BAPN administration and periaortic elastase application induced a chronic, advanced-stage AAA with characteristics of persistent aneurysm growth, thrombus formation, and spontaneous rupture. Future studies should use this model, especially for examining tissue remodeling during the late stages of aneurysm development.

Project description:ObjectiveMurine models have proved instrumental in studying various aspects of abdominal aortic aneurysm (AAA), from identification of underlying pathophysiologic changes to the development of novel therapeutic strategies. In the current study, we describe a new model in which an elastase-treated donor aorta is transplanted to a recipient mouse and allowed to progress to aneurysm. We hypothesized that by transplanting an elastase-treated abdominal aorta of one genotype to a recipient mouse of a different genotype, one can differentiate pathophysiologic factors that are intrinsic to the aortic wall from those stemming from circulation and other organs.MethodsElastase-treated aorta was transplanted to the infrarenal abdominal aorta of recipient mice by end-to-side microsurgical anastomosis. Heat-inactivated elastase-treated aorta was used as a control. Syngeneic transplants were performed with use of 12-week-old C57BL/6 littermates. Transplant grafts were harvested from recipient mice on day 7 or day 14 after surgery. The aneurysm outcome was measured by aortic expansion, elastin degradation, proinflammatory cytokine expression, and inflammatory cell infiltration and compared with that produced with the established, conventional elastase infusion model.ResultsThe surgical technique success rate was 75.6%, and the 14-day survival rate was 51.1%. By day 14 after surgery, all of the elastase-treated transplanted abdominal aortas had dilated and progressed to AAAs, defined as 100% or more increase in the maximal external diameter compared with that measured before elastase perfusion, whereas none of the transplanted aortas pretreated with inactive elastase became aneurysmal (percentage increase in maximum aortic diameter: 159.36% ± 23.27%, transplanted elastase, vs 41.46% ± 9.34%, transplanted inactive elastase). Aneurysm parameters, including elastin degradation and infiltration of macrophages and T lymphocytes, were found to be identical to those observed in the conventional elastase model. Quantitative polymerase chain reaction analysis revealed similarly increased levels of proinflammatory cytokines (relative changes of mRNA in the conventional elastase model vs transplant model: tumor necrosis factor α, 1.71 ± 0.27 vs 2.93 ± 0.86; monocyte chemoattractant protein 1, 2.36 ± 0.58 vs 2.87 ± 0.51; chemokine (C-C motif) ligand 5, 3.37 ± 0.92 vs 3.46 ± 0.83; and interferon γ, 3.09 ± 0.83 vs 5.30 ± 1.69). Using green fluorescent protein transgenic mice as donors or recipients, we demonstrated that a small quantity of mononuclear leukocytes in the transplant grafts bared the genotype of the donors.ConclusionsTransplanted elastase-treated abdominal aorta could develop to aneurysm in recipient mice. This AAA transplant model can be used to examine how the microenvironment of a transplanted aneurysmal aorta may be altered by the contributions of the "global" environment of the recipient.

Dataset Information

Hemodynamics and pathology of an enlarging abdominal aortic aneurysm model in rabbits.

Publications

Hemodynamics and pathology of an enlarging abdominal aortic aneurysm model in rabbits.

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