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

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.

Download Full-text

Porohyperelastic Simulation of Abdominal Aortic Aneurysms

ASME 2008 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2008-193147 ◽

2008 ◽

Author(s):

Avinash Ayyalasomayajula ◽

Bruce R. Simon ◽

Jonathan P. Vande Geest

Keyword(s):

Wall Stress ◽

Aortic Aneurysms ◽

Maximum Diameter ◽

Patient Specific ◽

Infrarenal Aorta ◽

Stress Studies ◽

Abdominal Aortic ◽

Peak Wall Stress ◽

Work Done

Abdominal aortic aneurysm (AAA) is a progressive dilation of the infrarenal aorta and results in a significant alteration in local hemodynamic environment [1]. While an aneurysmal diameter of 5.5cm is typically classified as being of high risk, recent studies have demonstrated that maximum wall stress could be a better indicator of an AAA rupture than maximum diameter [2]. The wall stress is greatly influenced by the blood pressure, aneurysm diameter, shape, wall thickness and the presence of thrombus. The work done by Finol et al. suggested that hemodynamic pressure variations have an insignificant effect on AAA wall stress and that primarily the shape of the aneurysm determines the stress distribution. They noted that for peak wall stress studies the static pressure conditions would suffice as the in vivo conditions. Wang et al have developed an isotropic hyperelastic constitutive model for the intraluminal thrombus (ILT). Such models have been used to study the stress distributions in patient specific AAAs [3, 4].

Download Full-text

Strain Mapping From Four-Dimensional Ultrasound Reveals Complex Remodeling in Dissecting Murine Abdominal Aortic Aneurysms

Journal of Biomechanical Engineering ◽

10.1115/1.4043075 ◽

2019 ◽

Vol 141 (6) ◽

Cited By ~ 4

Author(s):

Hannah L. Cebull ◽

Arvin H. Soepriatna ◽

John J. Boyle ◽

Sean M. Rothenberger ◽

Craig J. Goergen

Keyword(s):

Three Dimensional ◽

Small Animal ◽

Aortic Aneurysms ◽

Maximum Diameter ◽

High Frequency Ultrasound ◽

4D Ultrasound ◽

Abdominal Aortic ◽

Lagrange Strain ◽

Aortic Strain

Current in vivo abdominal aortic aneurysm (AAA) imaging approaches tend to focus on maximum diameter but do not measure three-dimensional (3D) vascular deformation or strain. Complex vessel geometries, heterogeneous wall compositions, and surrounding structures can all influence aortic strain. Improved understanding of complex aortic kinematics has the potential to increase our ability to predict aneurysm expansion and eventual rupture. Here, we describe a method that combines four-dimensional (4D) ultrasound and direct deformation estimation to compute in vivo 3D Green-Lagrange strain in murine angiotensin II-induced suprarenal dissecting aortic aneurysms, a commonly used small animal model. We compared heterogeneous patterns of the maximum, first-component 3D Green-Lagrange strain with vessel composition from mice with varying AAA morphologies. Intramural thrombus and focal breakage in the medial elastin significantly reduced aortic strain. Interestingly, a dissection that was not detected with high-frequency ultrasound also experienced reduced strain, suggesting medial elastin breakage that was later confirmed via histology. These results suggest that in vivo measurements of 3D strain can provide improved insight into aneurysm disease progression. While further work is needed with both preclinical animal models and human imaging studies, this initial murine study indicates that vessel strain should be considered when developing an improved metric for predicting aneurysm growth and rupture.

Download Full-text

Morphological and Biomechanical Differences in the Elastase and AngIIapoE−/−Rodent Models of Abdominal Aortic Aneurysms

BioMed Research International ◽

10.1155/2015/413189 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 19

Author(s):

Evan H. Phillips ◽

Alexa A. Yrineo ◽

Hilary D. Schroeder ◽

Katherine E. Wilson ◽

Ji-Xin Cheng ◽

...

Keyword(s):

Ex Vivo ◽

Aortic Aneurysms ◽

Circulating Biomarkers ◽

Induction Method ◽

Future Studies ◽

Disease Characteristics ◽

Abdominal Aortic ◽

Extracellular Matrix Molecules ◽

Biomechanical Parameters

An abdominal aortic aneurysm (AAA) is a potentially fatal cardiovascular disease with multifactorial development and progression. Two preclinical models of the disease (elastase perfusion and angiotensin II infusion in apolipoprotein-E-deficient animals) have been developed to study the disease during its initiation and progression. To date, most studies have usedex vivomethods to examine disease characteristics such as expanded aortic diameter or analytic methods to look at circulating biomarkers. Herein, we provide evidence fromin vivoultrasound studies of the temporal changes occurring in biomechanical parameters and macromolecules of the aortic wall in each model. We present findings from 28-day studies in elastase-perfused rats and AngIIapoE−/−mice. While each model develops AAAs specific to their induction method, they both share characteristics with human aneurysms, such as marked changes in vessel strain and blood flow velocity. Histology and nonlinear microscopy confirmed that both elastin and collagen, both important extracellular matrix molecules, are similarly affected in their levels and spatial distribution. Future studies could make use of the differences between these models in order to investigate mechanisms of disease progression or evaluate potential AAA treatments.

Download Full-text

Effect of Doxycycline on Survival in Abdominal Aortic Aneurysms in a Mouse Model

Contrast Media & Molecular Imaging ◽

10.1155/2021/9999847 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Lisa C. Adams ◽

Julia Brangsch ◽

Jan O. Kaufmann ◽

Dilyana B. Mangarova ◽

Jana Moeckel ◽

...

Keyword(s):

Angiotensin Ii ◽

Ex Vivo ◽

Endothelial Damage ◽

Aortic Aneurysms ◽

Clinical Dose ◽

Doxycycline Treatment ◽

Abdominal Aortic ◽

Significant Difference ◽

Aneurysm Growth

Background. Currently, there is no reliable nonsurgical treatment for abdominal aortic aneurysm (AAA). This study, therefore, investigates if doxycycline reduces AAA growth and the number of rupture-related deaths in a murine ApoE−/− model of AAA and whether gadofosveset trisodium-based MRI differs between animals with and without doxycycline treatment. Methods. Nine ApoE−/− mice were implanted with osmotic minipumps continuously releasing angiotensin II and treated with doxycycline (30 mg/kg/d) in parallel. After four weeks, MRI was performed at 3T with a clinical dose of the albumin-binding probe gadofosveset (0.03 mmol/kg). Results were compared with previously published wild-type control animals and with previously studied ApoE−/− animals without doxycycline treatment. Differences in mortality were also investigated between these groups. Results. In a previous study, we found that approximately 25% of angiotensin II-infused ApoE−/− mice died, whereas in the present study, only one out of 9 angiotensin II-infused and doxycycline-treated ApoE−/− mice (11.1%) died within 4 weeks. Furthermore, doxycycline-treated ApoE−/− mice showed significantly lower contrast-to-noise (CNR) values ( p = 0.017 ) in MRI compared to ApoE−/− mice without doxycycline treatment. In vivo measurements of relative signal enhancement (CNR) correlated significantly with ex vivo measurements of albumin staining (R2 = 0.58). In addition, a strong visual colocalization of albumin-positive areas in the fluorescence albumin staining with gadolinium distribution in LA-ICP-MS was shown. However, no significant difference in aneurysm size was observed after doxycycline treatment. Conclusion. The present experimental in vivo study suggests that doxycycline treatment may reduce rupture-related deaths in AAA by slowing endothelial damage without reversing aneurysm growth.

Download Full-text

Assessment of Elastase-Induced Murine Abdominal Aortic Aneurysms: Comparison of Ultrasound Imaging withIn SituVideo Microscopy

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/252141 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 15

Author(s):

Junya Azuma ◽

Lars Maegdefessel ◽

Toshiro Kitagawa ◽

Ronald L. Dalman ◽

Michael V. McConnell ◽

...

Keyword(s):

High Frequency ◽

Ex Vivo ◽

Linear Regression Analysis ◽

Intraclass Correlation ◽

Abdominal Aortic Aneurysms ◽

Aortic Aneurysms ◽

Control Group ◽

High Frequency Ultrasound ◽

Luminal Diameter ◽

Abdominal Aortic

Aims. The aim of this study was to definitively assess the validity of noninvasive high-frequency ultrasound (US) measurements of aortic luminal diameter (ALD) in a murine model of elastase-induced abdominal aortic aneurysm in comparison with in situ video microscopy (VM).Methods. C57BL/6 mice underwent transient perfusion of the aorta with either elastase (n=20: Elastase group) or saline (n=10: Sham). Unoperated mice (n=10) were also studied.Results. ALD measurements by US had excellent linear correlation and absolute agreement with that by VM in both Control (unoperated or sham-operated mice) and elastase groups (r=0.96, intraclass correlation coefficient(ICC)=0.88andr=0.93,ICC=0.92, resp.). Bland-Altman analysis of US compared with VM measurements in both groups indicated good agreement, however US measurements were slightly but significantly higher than VM measurements in the control group (mean bias 0.039 mm,P<.05). Linear regression analysis revealed excellent correlation between US and VM measurements in both groups. (R2=0.91in Control group,R2=0.85in elastase group.) The reliability of US measurements was also confirmed by ex vivo histological measurements.Conclusions.High-frequency US provides reliable ALD measurements in developing murine abdominal aortic aneurysms.

Download Full-text

Mechanical Stresses in Abdominal Aortic Aneurysms: Influence of Diameter, Asymmetry, and Material Anisotropy

Journal of Biomechanical Engineering ◽

10.1115/1.2898830 ◽

2008 ◽

Vol 130 (2) ◽

Cited By ~ 110

Author(s):

José F. Rodríguez ◽

Cristina Ruiz ◽

Manuel Doblaré ◽

Gerhard A. Holzapfel

Keyword(s):

Stress Analysis ◽

Strain Energy Function ◽

Peak Stress ◽

Wall Stress ◽

Aortic Aneurysms ◽

Maximum Diameter ◽

Material Anisotropy ◽

Tissue Samples ◽

Abdominal Aortic

Biomechanical studies suggest that one determinant of abdominal aortic aneurysm (AAA) rupture is related to the stress in the wall. In this regard, a reliable and accurate stress analysis of an in vivo AAA requires a suitable 3D constitutive model. To date, stress analysis conducted on AAA is mainly driven by isotropic tissue models. However, recent biaxial tensile tests performed on AAA tissue samples demonstrate the anisotropic nature of this tissue. The purpose of this work is to study the influence of geometry and material anisotropy on the magnitude and distribution of the peak wall stress in AAAs. Three-dimensional computer models of symmetric and asymmetric AAAs were generated in which the maximum diameter and length of the aneurysm were individually controlled. A five parameter exponential type structural strain-energy function was used to model the anisotropic behavior of the AAA tissue. The anisotropy is determined by the orientation of the collagen fibers (one parameter of the model). The results suggest that shorter aneurysms are more critical when asymmetries are present. They show a strong influence of the material anisotropy on the magnitude and distribution of the peak stress. Results confirm that the relative aneurysm length and the degree of aneurysmal asymmetry should be considered in a rupture risk decision criterion for AAAs.

Download Full-text

Porohyperelastic Finite Element Modeling of Abdominal Aortic Aneurysms

Journal of Biomechanical Engineering ◽

10.1115/1.4002370 ◽

2010 ◽

Vol 132 (10) ◽

Cited By ~ 31

Author(s):

Avinash Ayyalasomayajula ◽

Jonathan P. Vande Geest ◽

Bruce R. Simon

Keyword(s):

Finite Element ◽

Interstitial Fluid ◽

Fluid Velocity ◽

Aortic Aneurysms ◽

Maximum Diameter ◽

Hydraulic Permeability ◽

Infrarenal Aorta ◽

Standard Deviation Increase ◽

Fluid Velocities ◽

Abdominal Aortic

Abdominal aortic aneurysm (AAA) is the gradual weakening and dilation of the infrarenal aorta. This disease is progressive, asymptomatic, and can eventually lead to rupture—a catastrophic event leading to massive internal bleeding and possibly death. The mechanical environment present in AAA is currently thought to be important in disease initiation, progression, and diagnosis. In this study, we utilize porohyperelastic (PHE) finite element models (FEMs) to investigate how such modeling can be used to better understand the local biomechanical environment in AAA. A 3D hypothetical AAA was constructed with a preferential anterior bulge assuming both the intraluminal thrombus (ILT) and the AAA wall act as porous materials. A parametric study was performed to investigate how physiologically meaningful variations in AAA wall and ILT hydraulic permeabilities affect luminal interstitial fluid velocities and wall stresses within an AAA. A corresponding hyperelastic (HE) simulation was also run in order to be able to compare stress values between PHE and HE simulations. The effect of AAA size on local interstitial fluid velocity was also investigated by simulating maximum diameters (5.5 cm, 4.5 cm, and 3.5 cm) at the baseline values of ILT and AAA wall permeability. Finally, a cyclic PHE simulation was utilized to study the variation in local fluid velocities as a result of a physiologic pulsatile blood pressure. While the ILT hydraulic permeability was found to have minimal affect on interstitial velocities, our simulations demonstrated a 28% increase and a 20% decrease in luminal interstitial fluid velocity as a result of a 1 standard deviation increase and decrease in AAA wall hydraulic permeability, respectively. Peak interstitial velocities in all simulations occurred on the luminal surface adjacent to the region of maximum diameter. These values increased with increasing AAA size. PHE simulations resulted in 19.4%, 40.1%, and 81.0% increases in peak maximum principal wall stresses in comparison to HE simulations for maximum diameters of 35 mm, 45 mm, and 55 mm, respectively. The pulsatile AAA PHE FEM demonstrated a complex interstitial fluid velocity field the direction of which alternated in to and out of the luminal layer of the ILT. The biomechanical environment within both the aneurysmal wall and the ILT is involved in AAA pathogenesis and rupture. Assuming these tissues to be porohyperelastic materials may provide additional insight into the complex solid and fluid forces acting on the cells responsible for aneurysmal remodeling and weakening.

Download Full-text

Fluid-Solid Interaction Simulation of Flow and Stress Pattern in Thoracoabdominal Aneurysms: A Patient Specific Study

Volume 9: 6th FSI, AE and FIV and N Symposium ◽

10.1115/pvp2006-icpvt-11-93909 ◽

2006 ◽

Author(s):

Alessandro Borghi ◽

Nigel B. Wood ◽

Raad H. Mohiaddin ◽

X. Yun Xu

Keyword(s):

Wall Stress ◽

Aortic Aneurysms ◽

Maximum Diameter ◽

Patient Specific ◽

Specific Flow ◽

Hyperelastic Materials ◽

Abdominal Aortic ◽

Magnetic Resonance Imaging Mri ◽

Fluid Solid Interaction

Thoracoabdominal aneurysm (TA) is a pathology that involves the enlargement of the aortic diameter in the inferior descending thoracic aorta and has risk factors including aortic dissection, aortitis or connective tissue disorders (Webb, T. H. and Williams, G. M. 1999). Abnormal flow patterns and stress on the diseased aortic wall are thought to play an important role in the development of this pathology and the internal wall stress has proved to be more reliable as a predictor of rupture than the maximum diameter for abdominal aortic aneurysms (Fillinger, M. F., et al. 2003). In the present study, two patients with TAs of different maximum diameters were scanned using magnetic resonance imaging (MRI) techniques. Realistic models of the aneurysms were reconstructed from the in vivo MRI data acquired from the patients, and subject-specific flow conditions were applied as boundary conditions. The wall and thrombus were modeled as hyperelastic materials and their properties were derived from the literature. Fully coupled fluid-solid interaction simulations were performed for both cases using ADINA 8.2. Results were obtained for both the flow and wall stress patterns within the aneurysms. The results show that the wall stress distribution and its magnitude are strongly dependent on the 3-D shape of the aneurysm and the distribution of thrombus.

Download Full-text

[18F]Fluorothymidine Uptake in the Porcine Pancreatic Elastase-Induced Model of Abdominal Aortic Aneurysm

Journal of Imaging ◽

10.3390/jimaging7080130 ◽

2021 ◽

Vol 7 (8) ◽

pp. 130

Author(s):

Richa Gandhi ◽

Joanna Koch-Paszkowski ◽

Charalampos Tsoumpas ◽

Marc A. Bailey

Keyword(s):

Murine Model ◽

Ex Vivo ◽

Aortic Rupture ◽

Aortic Aneurysms ◽

Preclinical Model ◽

Pancreatic Elastase ◽

Abdominal Aortic ◽

Pet Ct ◽

Porcine Pancreatic Elastase

The porcine pancreatic elastase (PPE) model is a common preclinical model of abdominal aortic aneurysms (AAA). Some notable characteristics of this model include the low aortic rupture rate, non-progressive disease course, and infra-renal AAA formation. Enhanced [18F]fluorothymidine ([18F]FLT) uptake on positron emission tomography/computed tomography (PET/CT) has previously been reported in the angiotensin II-induced murine model of AAA. Here, we report our preliminary findings of investigating [18F]FLT uptake in the PPE murine model of AAA. [18F]FLT uptake was found to be substantially increased in the abdominal areas recovering from the surgery, whilst it was not found to be significantly increased within the PPE-induced AAA, as confirmed using in vivo PET/CT and ex vivo whole-organ gamma counting (PPE, n = 7; controls, n = 3). This finding suggests that the [18F]FLT may not be an appropriate radiotracer for this specific AAA model, and further studies with larger sample sizes are warranted to elucidate the pathobiology contributing to the reduced uptake of [18F]FLT in this model.

Download Full-text

Nanoparticle-based targeted delivery of pentagalloyl glucose reverses elastase-induced abdominal aortic aneurysm and restores aorta to the healthy state in mice

10.1101/2019.12.16.878017 ◽

2019 ◽

Author(s):

Saphala Dhital ◽

Naren R. Vyavahare

Keyword(s):

Targeted Delivery ◽

Aortic Aneurysms ◽

Control Group ◽

Infrarenal Aorta ◽

Abdominal Aortic ◽

Healthy State ◽

Pentagalloyl Glucose ◽

Life Threatening ◽

Gold Nps ◽

Elastic Lamina

ABSTRACTAimAbdominal aortic aneurysms (AAA) is a life-threatening weakening and expansion of the abdominal aorta due to inflammatory cell infiltration and gradual degeneration of extracellular matrix (ECM). There are no pharmacological therapies to treat AAA. We tested the hypothesis that nanoparticle (NP) therapy that targets degraded elastin and delivers anti-inflammatory, anti-oxidative, and ECM stabilizing agent, pentagalloyl glucose (PGG) will reverse advance stage aneurysm in an elastase-induced mouse model of AAA.Method and ResultsPorcine pancreatic elastase (PPE) was applied periadventitially to the infrarenal aorta in mice and AAA was allowed to develop for 14 days. Nanoparticles loaded with PGG (EL-PGG-NPs) were then delivered via IV route at 14-day and 21-day (10 mg/kg of body weight). A control group of mice received no therapy. The targeting of NPs to the AAA site was confirmed with fluorescent dye marked NPs and gold NPs. Animals were sacrificed at 28-d. We found that targeted PGG therapy reversed the AAA by decreasing matrix metalloproteinases MMP-9 and MMP-2, and the infiltration of macrophages in the medial layer. The increase in diameter of the aorta was reversed to healthy controls. Moreover, PGG treatment restored degraded elastic lamina and increased the circumferential strain of aneurysmal aorta to the healthy levels.ConclusionOur results support that site-specific delivery of PGG with targeted nanoparticles can be used to treat already developed AAA. Such therapy can reverse inflammatory markers and restore arterial homeostasis.

Download Full-text