Progressive Alterations in Biomechanical Response of a Mouse Model of Aneurysm

Abdominal aortic aneurysm (AAA) is a complex disease that leads to a localized dilation of the infrarenal aorta, the rupture of which is associated with significant morbidity and mortality, however the underlying mechanisms by which such changes remains an important unanswered question in the literature. Animal models of AAA can be used to study how changes in the microstructural and biomechanical behavior of aortic tissues develop as disease progresses in these animals. We chose here to investigate changes in mechanical characteristics with time in the established Apolipoprotein E deficient (ApoE−/−) angiotensin II (AngII) infused mouse model of AAA.

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Age-Related Differences in the Biaxial Biomechanical Behavior of Human Abdominal Aorta

Advances in Bioengineering ◽

10.1115/imece2002-32509 ◽

2002 ◽

Cited By ~ 2

Author(s):

Jonathan P. Vande Geest ◽

Michael S. Sacks ◽

David A. Vorp

Keyword(s):

Tensile Testing ◽

Mechanical Response ◽

Uniaxial Tensile ◽

Aortic Tissue ◽

Orthogonal Direction ◽

Biomechanical Behavior ◽

Uniaxial Tensile Testing ◽

Age Related ◽

Abdominal Aortic ◽

Biomechanical Response

The biomechanical response of abdominal aortic tissue to uniaxial loading conditions has been reported previously [1]. This testing identified the uniaxial mechanical response of aortic tissue to specimens oriented in the longitudinal and circumferential directions, but did not provide significant evidence for the isotropy or anisotropy of this tissue. The information taken from uniaxial tensile testing is insufficient for the characterization of the multi-axial mechanical response of aortic tissue. In particular, the uniaxial response of a biological tissue in a given direction does not incorporate the effects of loading in an orthogonal direction. For these reasons, there exists a need for an enhanced description of the mechanical response of aortic tissue to loading in multiple planar directions. For the current investigation, biaxial tensile testing was performed on normal abdominal aortic tissue in order to gain insight into the anisotropy and age related differences of the biomechanical response of this tissue.

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Protease Expression Colocalizes to Regions of Abdominal Aortic Expansion and Stiffening in a Murine Aneurysm Model

ASME 2008 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2008-190309 ◽

2008 ◽

Author(s):

Craig J. Goergen ◽

Dara Y. Kallop ◽

Charles A. Taylor ◽

Robby M. Weimer ◽

Joan M. Greve

Keyword(s):

Abdominal Aortic Aneurysm ◽

Vessel Wall ◽

Complex Disease ◽

Detailed Understanding ◽

The Poor ◽

Abdominal Aortic ◽

Underlying Mechanisms ◽

Aortic Stiffening ◽

Aneurysm Model ◽

Protease Expression

Abdominal aortic aneurysm (AAA) is a complex disease defined as a pathological dilation of the vessel wall to larger than 150% of normal. Although the poor clinical outcomes associated with this disease are well known, a detailed understanding of the underlying mechanisms that lead to AAA development and expansion remains elusive. The purpose of this study was to determine if areas of increased protease expression correspond to locations of aortic stiffening and enlargement in a commonly used mouse model [1].

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Biomechanical and Microstructural Analysis of Wildtype (C57BL6) Mouse Aorta

ASME 2011 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2011-53729 ◽

2011 ◽

Author(s):

Darren Haskett ◽

Greg Johnson ◽

Mohamad Azhar ◽

Jonathan Vande Geest

Keyword(s):

Disease Progression ◽

Microstructural Analysis ◽

Disease Process ◽

Infrarenal Aorta ◽

Unanswered Question ◽

C57bl6 Mouse ◽

Underlying Mechanisms ◽

Mouse Aorta ◽

Biomechanical Factors

It is generally accepted that the formation of an aneurysm in the infrarenal aorta is a complex and multi-factorial disease, however little is known about how biomechanical factors may play a role in the progression of aneurysmal disease. Although it is known that human aneurysmal tissue is remodeled in the disease process [1] and that such reorganization leads to altered function [2], the underlying mechanisms by which such changes remains an important unanswered question in the literature. The purpose of this study is to develop a means for determining the biomechanical alterations that occur within the aorta to better understand aneurysmal disease progression.

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Current evidence and prospects for medical treatment of abdominal aortic aneurysms

VASA ◽

10.1024/0301-1526.34.4.217 ◽

2005 ◽

Vol 34 (4) ◽

pp. 217-223 ◽

Cited By ~ 11

Author(s):

Diehm ◽

Schmidli ◽

Dai-Do ◽

Baumgartner

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Medical Treatment ◽

Endovascular Treatment ◽

Abdominal Aortic Aneurysms ◽

Aortic Aneurysms ◽

Current Evidence ◽

Significant Morbidity ◽

Abdominal Aortic ◽

Risk Of Rupture

Abdominal aortic aneurysm (AAA) is a potentially fatal condition with risk of rupture increasing as maximum AAA diameter increases. It is agreed upon that open surgical or endovascular treatment is indicated if maximum AAA diameter exceeds 5 to 5.5cm. Continuing aneurysmal degeneration of aortoiliac arteries accounts for significant morbidity, especially in patients undergoing endovascular AAA repair. Purpose of this review is to give an overview of the current evidence of medical treatment of AAA and describe prospects of potential pharmacological approaches towards prevention of aneurysmal degeneration of small AAAs and to highlight possible adjunctive medical treatment approaches after open surgical or endovascular AAA therapy.

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Dysregulation of DNA methylation during development as a potential mechanisms contributing to obsessive compulsive disorders and autism

10.31234/osf.io/udfya ◽

2019 ◽

Author(s):

German I. Todorov ◽

Karthikeyan Mayilvahanan ◽

David Ashurov ◽

Catarina Cunha

Keyword(s):

Mouse Model ◽

Autism Spectrum ◽

Obsessive Compulsive ◽

Cancer Treatments ◽

Knock Out ◽

Treatment Priority ◽

Underlying Mechanisms ◽

Knock Out Mice ◽

Obsessive Compulsive Disorders ◽

Compulsive Disorders

Autism Spectrum Disorder (ASD) is a pervasive developmental disorder, that is raising at a concerning rate. However, underlying mechanisms are still to be discovered. Obsessions and compulsions are the most debilitating aspect of these disorders (OCD), and they are the treatment priority for patients. SAPAP3 knock out mice present a reliable mouse model for repetitive compulsive behavior and are mechanistically closely related to the ASD mouse model Shank3 on a molecular level and AMPA receptor net effect. The phenotype of SAPAP3 knock out mice is obsessive grooming that leads to self-inflicted lesions by 4 months of age. Recent studies have accumulated evidence, that epigenetic mechanisms are important effectors in psychiatric conditions such as ASD and OCD. Methylation is the most studied mechanism, that recently lead to drug developments for more precise cancer treatments. We injected SAPAP3 mice with an epigenetic demethylation drug RG108 during pregnancy and delayed the onset of the phenotype in the offspring by 4 months. This result gives us clues about possible mechanism involved in OCD and ASD. Additionally, it shows that modulation of methylation mechanisms during development might be explored as a preventative treatment in the cases of high inherited risk of certain mental health conditions.

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Initial Clinical Experience With a New Conformable Abdominal Aortic Endograft: Aortic Neck Coverage and Curvature Analysis in Challenging Aortic Necks

Journal of Endovascular Therapy ◽

10.1177/1526602821996723 ◽

2021 ◽

pp. 152660282199672

Author(s):

Alice Finotello ◽

Richte Schuurmann ◽

Sara Di Gregorio ◽

Gian Antonio Boschetti ◽

Nabil Chakfé ◽

...

Keyword(s):

Aortic Wall ◽

Surface Coverage ◽

Infrarenal Aorta ◽

Technical Success ◽

Curvature Analysis ◽

Average Curvature ◽

Aortic Neck ◽

Abdominal Aortic ◽

Shortest Distance ◽

New Generation

Objectives: Aim of this work was to investigate precision of deployment and conformability of a new generation GORE EXCLUDER Conformable Endoprosthesis with active control system (CEXC Device, W.L. Gore and Associates, Flagstaff, AZ, USA) by analyzing aortic neck coverage and curvature. Methods: All consecutive elective patients affected by abdominal aortic aneurysm or aortoiliac aneurysm treated at our institution between November 2018 and June 2019 with the new CEXC Device were enrolled. Validated software was adopted to determine the available apposition surface area into the aortic neck, apposition of the endograft to the aortic wall, shortest apposition length (SAL), shortest distance between the endograft fabric and the lowest renal arteries (SFD) and between the endograft fabric and the contralateral renal artery (CFD). Pointwise centerline curvature was also computed. Results: Twelve patients (10 men, median age 78 years (71.75, 81.0)) with available pre- and postoperative computed tomography angiography (CTA) were included. Technical success was obtained in all the cases. Preoperative median length of the proximal aortic neck was 16.1 mm (10.7, 21.7) and suprarenal (α) and infrarenal (β) neck angulation were, respectively, 28.9° (15.7°, 47.5°) and 75.0° (66.9°, 81.4°). Postoperative median apposition surface coverage was 79% (69.25%, 90.75%) of the available apposition surface. SFD and CFD were 1.5 mm (0.75, 5.25) and 7 mm (4.5, 21.5), respectively. Average curvature over the infrarenal aorta decreased from 25 m−1 (21.75, 29.0) to 22.5 m−1 (18.75, 24.5) postoperatively (p=0.02). Maximum curvature did not decrease significantly from 64.5 m−1 (54.25, 92.0) to 62 m−1 (41.75, 71.5) (p=0.1). Conclusions: Our early experience showed that deployment of the CEXC Device is safe and effective for patients with challenging proximal aortic necks. Absence of significant changes between pre- and postoperative proximal aortic neck angulations and curvature confirms the high conformability of this endograft.

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Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation

Scientific Reports ◽

10.1038/s41598-021-92303-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

L. B. Steffensen ◽

J. Stubbe ◽

J. S. Lindholt ◽

H. C. Beck ◽

M. Overgaard ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Basement Membrane ◽

Protective Factor ◽

Complex Disease ◽

Artery Bypass ◽

Protective Role ◽

Collagen Iv ◽

Mammary Arteries ◽

Abdominal Aortic

AbstractAbdominal aortic aneurysm (AAA) is a complex disease which is incompletely accounted for. Basement membrane (BM) Collagen IV (COL4A1/A2) is abundant in the artery wall, and several lines of evidence indicate a protective role of baseline COL4A1/A2 in AAA development. Using Col4a1/a2 hemizygous knockout mice (Col4a1/a2+/−, 129Svj background) we show that partial Col4a1/a2 deficiency augmented AAA formation. Although unchallenged aortas were morphometrically and biomechanically unaffected by genotype, explorative proteomic analyses of aortas revealed a clear reduction in BM components and contractile vascular smooth muscle cell (VSMC) proteins, suggesting a central effect of the BM in maintaining VSMCs in the contractile phenotype. These findings were translated to human arteries by showing that COL4A1/A2 correlated to BM proteins and VSMC markers in non-lesioned internal mammary arteries obtained from coronary artery bypass procedures. Moreover, in human AAA tissue, MYH11 (VSMC marker) was depleted in areas of reduced COL4 as assessed by immunohistochemistry. Finally, circulating COL4A1 degradation fragments correlated with AAA progression in the largest Danish AAA cohort, suggesting COL4A1/A2 proteolysis to be an important feature of AAA formation. In sum, we identify COL4A1/A2 as a critical regulator of VSMC phenotype and a protective factor in AAA formation.

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Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001615 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001615

Author(s):

Rachel A Woolaver ◽

Xiaoguang Wang ◽

Alexandra L Krinsky ◽

Brittany C Waschke ◽

Samantha M Y Chen ◽

...

Keyword(s):

T Cell ◽

Mouse Model ◽

Immune Responses ◽

Single Cell ◽

T Cell Activation ◽

Antitumor Immunity ◽

Cell Activation ◽

Tcr Repertoire ◽

Underlying Mechanisms ◽

Personalized Cancer

BackgroundAntitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences.MethodsWe developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes.ResultsWe discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRβ sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status.ConclusionsWe reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.

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Demyelination and remyelination detected in an alternative cuprizone mouse model of multiple sclerosis with 7.0 T multiparameter magnetic resonance imaging

Scientific Reports ◽

10.1038/s41598-021-90597-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shuang Ding ◽

Yu Guo ◽

Xiaoya Chen ◽

Silin Du ◽

Yongliang Han ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Multiple Sclerosis ◽

Magnetic Resonance ◽

Mouse Model ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Blue Staining ◽

Resonance Imaging ◽

The Mean ◽

Underlying Mechanisms

AbstractThe aim of this study was to investigate the mechanisms underlying demyelination and remyelination with 7.0 T multiparameter magnetic resonance imaging (MRI) in an alternative cuprizone (CPZ) mouse model of multiple sclerosis (MS). Sixty mice were divided into six groups (n = 10, each), and these groups were imaged with 7.0 T multiparameter MRI and treated with an alternative CPZ administration schedule. T2-weighted imaging (T2WI), susceptibility-weighted imaging (SWI), and diffusion tensor imaging (DTI) were used to compare the splenium of the corpus callosum (sCC) among the groups. Prussian blue and Luxol fast blue staining were performed to assess pathology. The correlations of the mean grayscale value (mGSV) of the pathology results and the MRI metrics were analyzed to evaluate the multiparameter MRI results. One-way ANOVA and post hoc comparison showed that the normalized T2WI (T2-nor), fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) values were significantly different among the six groups, while the mean phase (Φ) value of SWI was not significantly different among the groups. Correlation analysis showed that the correlation between the T2-nor and mGSV was higher than that among the other values. The correlations among the FA, RD, MD, and mGSV remained instructive. In conclusion, ultrahigh-field multiparameter MRI can reflect the pathological changes associated with and the underlying mechanisms of demyelination and remyelination in MS after the successful establishment of an acute CPZ-induced model.

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