The purpose of this study was to determine whether androgen promotes AT1aR expression on smooth muscle to confer high prevalence of AngII-induced AAAs in hyperlipidemic mice. In addition, we also investigate the role of androgen in the progression of established AngII-induced AAAs. First, we sought to examine the role of endogenous androgen in the growth of established AngII-induced AAAs. By castrating male mice, we demonstrated that removal of endogenous androgen significantly decreased the progressive lumen dilation of established AngII-induced AAAs in male ApoE-/- mice, but had no effect on external AAA diameters. These results suggest that androgen contributes to the progression of established AAAs through distinct mechanisms that differentially influence aortic lumen and wall diameters. We also investigate whether androgen regulates aortic AT1aR expression to promote AngII-induced AAA formation. Our data demonstrated that in male and female mice, both endogenous and exogenous androgen stimulate AT1aR level particularly in abdominal aortas. This androgen-dependent enhanced expression of abdominal aortic AT1aR was correlated with increased AngIIinduced AAA formation in male and female mice. Smooth muscle AT1aR deficiency significantly reduced luminal and external diameters of abdominal aortas as well as the incidence of AngII-induced AAAs in adult female mice administered exogenous androgen. Collectively, these results indicate that in adult mice androgen stimulate smooth muscle AT1aR expression to promote AngII-induced AAA formation. To determine the role of androgen during development on AT1aR expression on SMC and AngII-induced vascular pathologies, we exposed neonatal female mice to one single dose of testosterone. Our data demonstrated that neonatal testosterone administration dramatically increased AngII-induced AAA, atherosclerosis and ascending aortic aneurysms in adult female mice. In addition, smooth muscle AT1aR deficiency reduced effects of neonatal testosterone to promote AAAs, but had no effect on the other two AngII-induced vascular pathologies. In summary, our findings demonstrated that androgen, both in adult life and during development, stimulate smooth muscle AT1aR expression and promote AngII-induced AAA in female hyperlipidemic mice.

This project concerns an exploration of the presence and interactions of long non-coding RNA transcripts in an experimental atherosclerosis mouse model with relevance for human abdominal aortic aneurysm development. 187 long noncoding RNAs, two of them entirely novel, were found to be differentially expressed between angiotensin II treated (developing abdominal aortic aneurysms) and non-treated apolipoprotein E deficient mice (not developing aneurysms) harvested after the same period of time. These transcripts were also studied with regards to co-expression network connections. Eleven previously annotated and two novel long non-coding RNAs were present in two significantly disease correlated co-expression groups that were further profiled with respect to network properties, Gene Ontology terms and MetaCore© connections.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Objectives: Clinical implementation of 3D ultrasound (3D-US) in vascular surgery is in its infancy. The aim of this thesis was to develop novel clinical applications for 3D-US in the diagnosis and management of abdominal aortic aneurysm (AAA). Methods: Four principle clinical applications were investigated. 1) Intraoperative imaging – The ability of 3D-US to detect and classify endoleaks was compared with digital subtraction angiography in patients undergoing EVAR. 2) Detection and classification of endoleaks following endovascular aneurysm repair (EVAR) – The abilityof 3D-US to accurately detect and classify endoleaks following EVAR was compared to CTA and the final multi-disciplinary team decision. 3) AAA volume measurement – measurements using magnetic and optically-tracked 3D-US were compared to CTA. 4) Biomechanical analysis – the challenges of using 3D-US to generate surface models for biomechanical simulation was explored by development of an interactive segmentation technique and comparison of paired CT and 3D-US datasets. Optimal results were used in finite element analysis (FEA) and computational fluid dynamic(CFD) simulations. Results: 3D-US out-performed uniplanar angiography for the detection of endoleaks during EVAR. This approach allowed contrast-free EVAR to be performed in patients with poor renal function. 3D contrast-enhanced ultrasound was superior to CTA for endoleak detection and classification when compared with the final decision of the multi-disciplinary team. Optimal results for AAA volume measurements were gained using an optically tracked 3D-US system in EVAR surveillance. However, there remained a significant mean difference of 13.6ml between CT and 3D-US. Complete technical success of generating geometries for use in biomechanical analysis using 3D-US was only 5%. When the optimal results were used, a comparable CFD analysis under the conditions of steady, laminar and Newtonian flow was achieved. Using basic modelling assumptions in FEA, peak von Mises and principle wall stress was found to be at the same anatomical location on both the CT and 3D-US models but the 3D-US model overestimated the wall stress values by 41% and 51% respectively. Conclusions: 3D-US could be clinically implemented for intra-operative imaging and EVAR surveillance in specific cases. 3D-US volume measurement is feasible but future work should aim to improve accuracy and inter-observer reliability. Although the results of biomechanical analysis using the optimal results was encouraging and provided a proof-of-principal, there are a number of technical developments required to make this approach feasible in a larger number of patients.

Orientadores: Sebastião Araujo, Ana Terezinha Guillaumon / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-13T22:15:18Z (GMT). No. of bitstreams: 1 Carvalho_AdrianaCamargo_M.pdf: 1640507 bytes, checksum: d217bd19f4b6097e48dac1bb2f824e35 (MD5) Previous issue date: 2009 / Resumo: Objetivos: Avaliar os níveis plasmáticos de vasopressina (AVP) em pacientes submetidos à correção cirúrgica não-complicada de aneurisma de aorta abdominal (AAA). Desenho: Estudo prospectivo, descritivo, observacional. Intervenções: Nenhuma. Local: Hospital de Clínicas da Unicamp. Métodos: A AVP plasmática foi mensurada por radio-imuno-ensaio em 22 pacientes não-consecutivos submetidos à correção cirúrgica convencional de AAA infra-renal, sob anestesia combinada (geral e epidural) nos seguintes tempos: pré-operatório (T0); 2h (T1) e 6h (T2) após o término da cirurgia; e nas manhãs do 1º (T3), 2º (T4) e 3º (T5) dia pós-operatório (PO). Algumas variáveis clínicas e laboratoriais de interesse foram registradas concomitantemente. Resultados: A idade média dos pacientes foi de 68,2±10,2 anos (variando de 49-82 anos), sendo 17 homens e 5 mulheres. Os níveis plasmáticos de AVP (média±DP pg/mL) estavam baixos e dentro da faixa de normalidade em T0 (1,4±0,7; controle), aumentando significativamente em T1 (62,6±62,9; p<0,001) e T2 (31,5±49,7; p<0,001), com uma queda exponencial a seguir, retornando aos níveis basais em T5 (2,1±3,8; p = NS). Correlações positivas e estatisticamente significativas foram encontradas entre a AVP e a glicemia, lactatemia e leucócitos sangüíneos, mas não com a pressão arterial sistêmica ou osmolaridade plasmática no PO. Conclusões: O padrão de aumento da AVP plasmática, com picos nas primeiras horas de PO nestes pacientes, sugere que esta resposta está diretamente relacionada ao trauma cirúrgico, mas não às alterações hemodinâmicas e da osmolaridade plasmática. A fisiopatologia deste padrão de resposta ao estresse é ainda obscuro, e merece investigações adicionais em procedimentos cirúrgicos gerais / Abstract: Objectives: To evaluate plasma vasopressin (AVP) levels in patients undergoing uncomplicated conventional abdominal aortic aneurysm (AAA) repair. Design: Prospective, descriptive, observational study. Interventions: None. Setting: A tertiary academic hospital at Campinas, Sao Paulo, Brazil. Methods: Plasma AVP concentrations were measured by radioimmunoassay in 22 nonconsecutive adult patients undergoing infra-renal AAA repair under combined general and epidural anesthesia at the following moments: pre-operative (T0); 2h (T1) and 6h (T2) after surgical procedure; and by the morning at the 1st (T3), 2nd (T4) and 3rd (T5) postoperative days. Some clinical and laboratory variables were concomitantly recorded. Results: Patients mean age was 68.2±10.2 years (ranging 49-82 years), with 17 males and 05 females. AVP plasma levels (mean±SD pg/mL) were low and within the normal range at T0 (1.4±0.7; control), showing a significant increase at T1 (62.6±62.9; p<0.001) and at T2 (31.5±49.7; p<0.001), with a marked progressive fall in the subsequent days, returning to basal levels at T5 (2.1±3.8; p = NS). Positive and statistically significant correlations were found between AVP levels and glycemia, lactatemia and white blood cells counts, but not with systemic arterial pressure or plasma osmolarity during postoperative period. Conclusions: The pattern of plasma AVP increasing, peaking during the 1st postoperative hours, suggests that this response is directly related to the surgical trauma, but not to hemodynamic and/or plasmatic osmolarity derangements. The pathophysiology of this pattern of stress response is still unclear, and deserves further investigation in general surgical procedures / Mestrado / Pesquisa Experimental / Mestre em Cirurgia

Abdominal Aortic Aneurysm (AAA) rupture remains a leading cause of death in westernized countries. Much remains to be understood on the biomechanics of rupture. It is not clear whether rupture is predominantly a phenomenon at the material level (aneurysm wall weakening) or due to abnormally elevated tissue wall tension (stress resultant). A computational study involving 4 ruptured and 9 unruptured abdominal aortic aneurysms (AAA) was conducted to test if ruptured aneurysms were subject to a higher pressure induced wall tension than unruptured aneurysms. The unique aspect of this study is that, regional variations in material properties (thickness, stiffness, failure strength) were documented in all the aneurysms in the study population. In addition, AAA geometry was documented using photographs from multiple rotational angles. Novel methods were developed for 3D reconstruction from photographs using voxel carving, for precise spatial mapping of measured properties onto the reconstructed 3D models and for scattered data interpolation of sparsely measured parameters to the entire finite element model. Heterogeneous, variable wall thickness models of patient-specific AAA were developed and the tension distribution under normal systolic pressure computed. Peak wall tension was the primary metric studied. Other indices found in literature (peak wall stress, peak regional tension to failure tension ratio and peak regional stress to failure stress ratio) were also compared. The peak wall tension in the ruptured aneurysm group was not higher than the unruptured aneurysms with statistical significance, but with a trend toward it (p = 0.053). Among the other metrics, the peak regional tension and stress ratios (with their respective failure counterparts) were higher in the ruptured group (p = 0.038 for both) but not so for peak wall stress (p = 0.099). Although rigorously studied, the small study population does not warrant definitive conclusions. The study methods developed however will permit larger studies of this nature to better investigate mechanisms in AAA rupture.

<div>An abdominal aortic aneurysm (AAA) is a pathological dilation of the abdominal aorta, as defined by a 50% increase in diameter or a diameter greater than 3 cm. While typically asymptomatic, there is a risk that the AAA will rupture, causing massive hemorrhaging and high mortality rates. Thus, once detected, the clinician must choose between surveillance and elective surgical repair. The first option carries the risk of rupture; the second risks complications and graft failure. Currently, clinical metrics of rupture risk are dependent on diameter and growth rate. However, a number of studies have indicated that, although rupture risk does increase with increased diameter, there are also a large number of patients with aneurysms for which the diameter criteria is insufficient. There remains a strong need to 1) determine better estimates of rupture risk in order to accurately assess the need for surgery and 2) improve surgical treatment to reduce perioperative risk. </div><div><br></div><div>Herein, we use ultrasound in mice to address these two prevalent uncertainties in aneurysm development and treatment. First, we further develop a murine aneurysm model that forms large aneurysms with distal thrombus. To increase the applicability of the model, we modulate aneurysm growth by altering elastase concentration and lysyl oxidase inhibition. We show that initial elastase concentration impacts aneurysm size, which is driven in part by a change in the degree of initial degradation of the aortic wall. We also demonstrate that lysyl oxidase inhibition (via BAPN) remains necessary for expansion even after the initial aneurysm formation and that removal of the lysyl oxidase inhibitor effectively stops growth in this model. As a final point, we show that female mice develop larger aneurysms than the males using this model. Then, with the aim of improving surgical treatment options, we explore the patency of various design parameters involved in tissue-engineered vascular grafts. To do so, we assess the allowable parameter design space of murine textile arterial grafts, so as to lead to better selection of key design components. Overall, the findings in this thesis demonstrate the applicability of ultrasound in small animals to improve aneurysm diagnostic and treatment options.</div>

La physiopathologie de l’anévrysme de l’aorte abdominale (AAA) est complexe. Elle implique notamment des facteurs hémodynamiques, une protéolyse matricielle, un stress oxydatif et une réaction immune. Des modèles expérimentaux ont été mis au point pour explorer les mécanismes impliqués dans la genèse et la croissance des AAAs. Dans ce travail, nous explorons le rôle de ces modèles dans la compréhension du remodelage vasculaire des AAAs. Dans une première partie, une revue de la littérature sur les modèles expérimentaux d’AAA est menée. Dans une seconde partie, nous explorons l’origine et le rôle des calcifications des AAAs expérimentaux. Dans une troisième partie, le modèle de xénogreffe aortique décellularisée est utilisé pour étudier le rôle de l’immunité adaptative dans la rupture. Notre revue identifie les principaux modèles d’AAA. Leur limite majeure est la survenue d’une cicatrisation empêchant l’évolution vers la rupture. Notre exploration des calcifications anévrysmales retrouve une co-localisation des calcifications avec de l’ADN libre et un modèle expérimental démontre la capacité de l’ADN libre à induire des calcifications. La croissance anévrysmale est toutefois ralentie par les calcifications. Notre étude sur le modèle de xénogreffe décellularisée retrouve la possibilité d’induire une rupture lorsqu’une pré-sensibilisation contre la matrice extracellulaire est réalisée. Les glycoprotéines de structure et les protéoglycanes semblent être les composants matriciels en cause dans ces ruptures. Les modèles expérimentaux constituent des outils majeurs pour l’étude des mécanismes impliqués dans le remodelage vasculaire des AAAs. / Pathophysiology of abdominal aortic aneurysms (AAA) is complex. It mainly involves hemodynamics, matrix proteolysis, oxidative stress and an immune reaction. Several experimental models have been described to explore mechanisms involved in this disease. In the present work, we explore the role of experimental models in AAA vascular remodeling. First, a literature review regarding experimental models of AAA is performed. Second, we explore the origin and the role of calcifications observed in experimental models. Third, the decellularized xenograft model is used to study the role of adaptive immunity in triggering rupture. Our review identifies main AAA models. Their major limit is aortic healing, preventing evolution toward rupture. We find that AAA calcifications co-localized with free DNA and that free DNA could induce calcifications experimentally. However, AAA growth is decreased by calcifications. The decellularized xenograft model can evolve toward rupture when pre-sensitization against the extracellular matrix is performed. Structural glycoproteins and proteoglycans seems to be the main matrix component involved in these ruptures. Experimental AAA models are major tools to study mechanisms involved in vascular remodeling.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20801号 / 医博第4301号 / 新制||医||1025(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 松田 道行, 教授 山下 潤, 教授 宮本 享 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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