Dataset Information

Animal Model Dependent Response to Pentagalloyl Glucose in Murine Abdominal Aortic Injury.

ABSTRACT: Abdominal aortic aneurysms (AAAs) are a local dilation of the aorta and are associated with significant mortality due to rupture and treatment complications. There is a need for less invasive treatments to prevent aneurysm growth and rupture. In this study, we used two experimental murine models to evaluate the potential of pentagalloyl glucose (PGG), which is a polyphenolic tannin that binds to and crosslinks elastin and collagen, to preserve aortic compliance. Animals underwent surgical aortic injury and received 0.3% PGG or saline treatment on the adventitial surface of the infrarenal aorta. Seventeen mice underwent topical elastase injury, and 14 mice underwent topical calcium chloride injury. We collected high-frequency ultrasound images before surgery and at 3-4 timepoints after. There was no difference in the in vivo effective maximum diameter due to PGG treatment for either model. However, the CaCl2 model had significantly higher Green-Lagrange circumferential cyclic strain in PGG-treated animals (p < 0.05). While ex vivo pressure-inflation testing showed no difference between groups in either model, histology revealed reduced calcium deposits in the PGG treatment group with the CaCl2 model. These findings highlight the continued need for improved understanding of PGG's effects on the extracellular matrix and suggest that PGG may reduce arterial calcium accumulation.

SUBMITTER: Anderson JL

PROVIDER: S-EPMC7827576 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Animal Model Dependent Response to Pentagalloyl Glucose in Murine Abdominal Aortic Injury.

Anderson Jennifer L JL Niedert Elizabeth E EE Patnaik Sourav S SS Tang Renxiang R Holloway Riley L RL Osteguin Vangelina V Finol Ender A EA Goergen Craig J CJ

Journal of clinical medicine 20210109 2

Abdominal aortic aneurysms (AAAs) are a local dilation of the aorta and are associated with significant mortality due to rupture and treatment complications. There is a need for less invasive treatments to prevent aneurysm growth and rupture. In this study, we used two experimental murine models to evaluate the potential of pentagalloyl glucose (PGG), which is a polyphenolic tannin that binds to and crosslinks elastin and collagen, to preserve aortic compliance. Animals underwent surgical aortic ...[more]

PMID: 33435461

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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.

Project description:ObjectivesUsing maximum diameter of an abdominal aortic aneurysm (AAA) alone for management can lead to delayed interventions or unnecessary urgent repairs. Abdominal aortic aneurysm stiffness plays an important role in its expansion and rupture. In vivo aortic magnetic resonance elastography (MRE) was developed to spatially measure AAA stiffness in previous pilot studies and has not been thoroughly validated and evaluated for its potential clinical value. This study aims to evaluate noninvasive in vivo aortic MRE-derived stiffness in an AAA porcine model and investigate the relationships between MRE-derived AAA stiffness and (1) histopathology, (2) uniaxial tensile test, and (3) burst testing for assessing MRE's potential in evaluating AAA rupture risk.Materials and methodsAbdominal aortic aneurysm was induced in 31 Yorkshire pigs (n = 226 stiffness measurements). Animals were randomly divided into 3 cohorts: 2-week, 4-week, and 4-week-burst. Aortic MRE was sequentially performed. Histopathologic analyses were performed to quantify elastin, collagen, and mineral densities. Uniaxial tensile test and burst testing were conducted to measure peak stress and burst pressure for assessing the ultimate wall strength.ResultsMagnetic resonance elastography-derived AAA stiffness was significantly higher than the normal aorta. Significant reduction in elastin and collagen densities as well as increased mineralization was observed in AAAs. Uniaxial tensile test and burst testing revealed reduced ultimate wall strength. Magnetic resonance elastography-derived aortic stiffness correlated to elastin density (ρ = -0.68; P < 0.0001; n = 60) and mineralization (ρ = 0.59; P < 0.0001; n = 60). Inverse correlations were observed between aortic stiffness and peak stress (ρ = -0.32; P = 0.0495; n = 38) as well as burst pressure (ρ = -0.55; P = 0.0116; n = 20).ConclusionsNoninvasive in vivo aortic MRE successfully detected aortic wall stiffening, confirming the extracellular matrix remodeling observed in the histopathologic analyses. These mural changes diminished wall strength. Inverse correlation between MRE-derived aortic stiffness and aortic wall strength suggests that MRE-derived stiffness can be a potential biomarker for clinically assessing AAA wall status and rupture potential.

Dataset Information

Animal Model Dependent Response to Pentagalloyl Glucose in Murine Abdominal Aortic Injury.

Publications

Animal Model Dependent Response to Pentagalloyl Glucose in Murine Abdominal Aortic Injury.

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