The rupture of an aneurysm in subarachnoid hemorrhage (SAH) is a dramatic event causing a severe impact on the brain and a transient or permanent ischemic condition. Several types of responses to meet the challenges of SAH have been found in the acute phase, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system, elevated levels of brain natriuretic peptide (BNP), and disturbances in cerebral and systemic metabolism. Cerebral metabolism and the endocrine stress response in the ultra-early phase was investigated in a novel porcine model of SAH in which autologous blood was injected to the anterior skull base. Early activation of the HPA axis was found with rapid elevation of adrenocorticotrophic hormone, cortisol and aldosterone. The peak values of these hormones were early and may be impossible to catch in patients. There were indications of a sympathetic nervous response with excretion of catecholamines in urine as well as plasma chromogranin-A elevation. Cerebral microdialysis suggested immediate substrate failure followed by hypermetabolism of glucose. The animal model seems suited for further studies of aneurysmal SAH. NT-proBNP was investigated in 156 patients with SAH, there was a dynamic course with increasing levels during the first 4 days of the disease. Factors predicting high NT-proBNP load included female sex, high age, high Troponin-I at admission, angiographic finding of an aneurysm and worse clinical condition at admission. High levels of NT-proBNP were correlated to factors indicating a more severe disease, suggesting the initial injury in aneurysmal SAH is an important factor in predicting high NT-proBNP during the acute stage of the disease. Measurements with indirect calorimetry were performed daily during the first week after SAH on 32 patients with SAH. There was a dynamic course with increasing energy expenditure (EE) the first week after SAH. Comparisons with three predictive equations indicated that measured EE generally is higher than predicted, but considerable variation exists within and between patients, indicating that prediction of EE in SAH is difficult. Altogether, the studies demonstrate a complicated response in acute SAH that needs to be further studied to increase possibility of good outcome in SAH patients.

Animal models of ocular hypertension are important for glaucoma research but come with experimental costs. Available methods of intraocular pressure (IOP) elevation are not always successful, the amplitude and time course of IOP changes are unpredictable and irreversible, and IOP measurement by tonometry is laborious. This dissertation focuses on the development and implementation of two novel systems for monitoring and controlling IOP without these limitations. The first device consists of a cannula implanted in the anterior chamber of the eye, a pressure sensor that continually measures IOP, and a bidirectional pump driven by control circuitry that can infuse or withdraw fluid to hold IOP at user-desired levels. A portable version was developed for tethered use on rats. The system was fully characterized and deemed ready for cage- or bench-side applications. The results lay the foundation for an implantable version that would give glaucoma researchers unparalleled knowledge and control of IOP in rats and potentially larger animals. Moreover, a novel mathematical technique was developed to efficiently analyze IOP records obtained using the pressure controlling device. The algorithm successfully yields the value of several parameters that influence ocular physiology and are commonly linked to glaucoma development. This unique methodology uses information regarding the amount of volume necessary to maintain IOP at different levels to quantify the outflow facility of perfused eyes. The use of this technology largely simplifies the investigator’s experimental set-up and cuts procedural times in half. The second device is an implantable pressure sensor for continuously monitoring IOP. The miniature system is equipped with pressure and temperature transducers, on-board amplifiers and a powerful microcontroller that ensure data quality. The sensor is able to obtain measurements with twice the accuracy and precision of any other IOP sensor used to date, avoid electronic drifts commonly seen in commercial sensing devices, and can potentially be used in a variety of animal models. The sensor was characterized and tested in alert rats for weeks on end. Data obtained with this device showed the presence of previously reported circadian rhythms, with IOP significantly increasing during nocturnal cycles. This technology provides researchers with an unprecedented tool to analyze IOP dynamics over time. The characterization of the amplitude, period and phase of the IOP profiles of normal and glaucomatous eyes may help establish a definitive correlation between ocular hypertension and glaucoma progression. While implantable systems provide investigators with essential physiological data, their implementation can be difficult. Challenges such as reduced operational lifetimes and limited data acquisition capabilities are commonly faced by most bio-devices. These limitations are frequently linked to small battery capacities, however the implementation of bigger batteries is not usually viable due to size requirements. Energy harvesting technologies have surfaced in recent years in an attempt to replace battery applications; however, most technologies provide low power densities and cannot deliver continuous telemetric operation. An innovative wireless powering system was developed to overcome these limitations. The technology uses radio frequency (RF) energy transfer to continuously harvest high energy levels. Taking advantage of the controlled environment under which most research animals are housed, RF transmitters are placed around the cage to form strong, omnidirectional electric fields. An especial antenna was designed to be worn by the animal and collect large energy levels, irrespective of animal movements and positioning. The system was tested on the implantable IOP sensor for weeks, providing robust performances and allowing the sensor to collect data continuously with high precision. The device consistently generated power densities much greater than those required by the sensor. The surplus of energy could be used to operate multiple sensors simultaneously, greatly increasing the investigator’s leverage. The technology is easily adaptable to other bio-sensors and has the potential to revolutionize the biomedical field.

Background: Age is an important risk factor for rheumatoid arthritis (RA), which often develops in middle age. However, how age-associated changes in immunity impact RA is poorly understood. Gut microbiota are known to be involved in the pathogenesis of RA, but the effects of microbiota in older subjects remain mostly unknown. Methods: We used segmented filamentous bacteria (SFB), a gut commensal species with immunomodulatory effects, and K/BxN mice, a T cell receptor (TCR) transgenic model, to study the effect of age and microbiota on autoimmune arthritis. Comparing young and middle-aged K/BxN T cells of the same TCR specificity allows us to study T cells with an age focus eliminating a key variable: TCR repertoire alteration with age. In addition to joints, we also studied pathological changes in the lung, an important extra-articular RA manifestation. We used flow cytometry to evaluate T follicular helper (Tfh) and T helper 17 (Th17) cells, as they both contribute to autoantibody production, a key disease index in both RA and K/BxN arthritis. Results: Middle-aged K/BxN mice had aggravated arthritis and pathological changes in the lung compared to young mice. Middle-aged mice displayed a strong accumulation of Tfh but not Th17 cells, and had defective Th17 differentiation and low expression of interleukin-23, a critical cytokine for Th17 maintenance. Although a soaring Tfh cell population accompanied by robust germinal center B cell responses were found in middle-aged mice, there was decreased cycling of Tfh cells, and SFB only induced the non-Tfh cells to upregulate Bcl-6, the Tfh master transcription factor, in the young but not the middle-aged group. Finally, the accumulated Tfh cells in middle-aged mice had an effector phenotype (CD62LloCD44hi). Conclusion: Age-dependent Tfh cell accumulation may play a crucial role in the increased autoimmune disease phenotype in middle-age. SFB, a potent stimulus for inducing Tfh differentiation, fails to promote Tfh differentiation in middle-aged K/BxN mice, suggesting that most of the middle-aged Tfh cells with an effector phenotype are Tfh effector memory cells induced at an earlier age. Our results also indicate that exposure to immunomodulatory commensals may allow the young host to develop an overactive immune system reminiscent of that found in the middle-aged host.

Parkinson's disease (PD) is a neurodegenerative disorder that is characterised by uncontrollable shaking, muscular rigidity and cognitive impairment, due to low levels of dopamine caused by loss of dopamine containing neurons (DCN). The loss of DCN has been strongly associated with Caspase mediated apoptotic death. At present there are many studies that indicate exercise is beneficial in PD treatment, but there is a lack of research exploring the potential pathways, which exercise can activate and suppress to provide such positive and even negative effects. This study is the first to explore the effect of treadmill exercise on the level of Caspases, along with CAMK-IV protein in different brain regions of MPTP-treated rat model, using WB analysis. The results of this research has demonstrated reduction or completely suppression of some active Caspases, as well as, elevated amount of CAMK-IV in different brain regions of exercised PD animal model. To determine how exercise is reducing and inhibiting activation of Caspases, the first step was to identify how Caspases are stimulated, using ReNcell VM stem cell line that had been differentiated and treated with 6OHDA. The results of the study demonstrated 6OHDA triggered Caspase mediated apoptotic death of dDCN via PERK ER stress and NFκB classical pathway. IF, WB and cell viability analysis, using a wide range of inhibitors, showed that Caspase-2 is activated by the PERK pathway of ER stress and NFB classical pathway in 6OHDA treated dDCN. 6OHDA triggered activation of Caspase- 8 by the classical pathway in NFB mediated death of dDCN. 6OHDA triggered Caspase-4 activation but the exact mechanism involved remains to be identified. Only through understanding the molecular pathways regulating death of DCN in PD, new potential targets for therapy may be identified, which may ultimately reduce further death of DCN and slow PD progression. This proposed study has the potential to seek for more efficient drugs, which can suppress Caspase activation by targeting key targets in the pathways that the Caspases follow. These new specific targeted drugs could be used with treadmill exercise to achieve maximum effect, by slowing down or inhibiting further death of DCN.

La leptospirose est une zoonose ré-émergente de distribution mondiale, causée par un spirochète du genre Leptospira. L'OMS rapporte environ un million de cas sévères de leptospirose humaine par an à travers le monde, avec un taux de mortalité de 10 %. Les rongeurs étant considérés comme les principaux hôtes réservoirs de cette bactérie, la transmettent aux Hommes et aux animaux, par un contact direct ou indirect via de l'urine infectée. Le rat brun (Rattus norvegicus) est important d'un point de vue épidémiologique car il est réservoir du principal sérogroupe incriminé dans les cas de leptospirose humaine : le sérogroupe Icterohaemorrhagiae. Chez ce rongeur, l'infection est asymptomatique et a été caractérisée par des modèles expérimentaux centrés sur la colonisation rénale des leptospires faisant appel à une voie d'inoculation éloignée des conditions naturelles. De plus, les détails sur la dynamique de transmission rat-rat restent encore inconnus. Il est donc important de mieux comprendre le rôle du rat dans le maintien des leptospires dans l'environnement, afin de mieux contrôler les épidémies de leptospirose humaine et animale. À partir d'un modèle expérimental avec une voie d'inoculation mimant des conditions naturelles (conjonctivale ou sous-cutanée), nous avons mis en évidence que la réponse sérologique semblerait être indépendante de la mise en place de la colonisation rénale, et que la voie conjonctivale serait plus efficace pour devenir porteur rénal que la voie sous-cutanée. De plus, une étude de l'infection naturelle sur le terrain avec les mêmes méthodes d'analyse, a permis de mettre en évidence la présence de leptospires dans les poumons de manière concomitante à un portage rénal chez le même individu. Grâce à la mise au point d'une nouvelle méthode de typage moléculaire, nous avons identifié les souches circulantes de leptospires dans une population urbaine de rats et leur dynamique de transmission. Toutes les souches portées par les rats appartenaient au sérogroupe Icterohaemorrhagiae et chaque colonie de rat ne semblait maintenir qu'une seule souche de leptospires dans sa population / The leptospirosis is a zoonosis caused by spirochetes of the genus Leptospira, which could infect human and animals. This infection represents a major problem of public health in several countries. The WHO estimates at one million of severe cases of human leptospirosis by year in the world, with a 10 % fatality rate. In the human, the leptospirosis is a mortal infection if it is not treated. The rodents, including the brown rat (Rattus norvegicus), are considered as a carrier and excrete pathogenic leptospires via urine, which becomes the main source of direct or indirect contamination of human and animal. In the rat, the asymptomatic infection was few characterized by experimental model, or only focused on the renal colonization using a no-natural inoculation route. Furthermore, the details of the transmission rat-rat remain still unknown. It is important to know the role of the rat in the persistence of leptospires in rural or urban environments, in order to better control leptospirosis epidemics. With an experimental model using conjunctival and subcutaneous routes, we showed that the antibodies production was independent of the rate of renal colonization and that the conjunctival route was more efficient to become renal carrier than the subcutaneous route. Furthermore, a study of the characteristics of natural infection using the same methods showed the presence of leptospires in lung of rat which are renal carriers. With a new method of molecular typing, we have studied the circulating of the Leptospira strains in the rat’s urban population. All the strains belonged to the Icterohaemorrhagiae serogroup and every colony of rats maintained only one strain of Leptospira. The characterization of the infection with the experimental and field studies, and the epidemiological studies are also important to model the infection in the brown rat, for the prevention of human and animal leptospirosis

Les maladies neurodégénératives sont un sujet de santé publique majeur. La maladie de Parkinson (MP), la démence à corps de Lewy (DCL) et l'atrophie multisystématisée (AMS) font partie d'une famille liées à l'accumulation pathologique d'une protéine : l'α-synucléine (α-syn), appelées les synucléinopathies. Il n'existe pas méthode de diagnostic formel pre-mortem de ces pathologies. À ce jour, la confirmation définitive de synucléinopathies n'est possible que sur des études post-mortem. Le mécanisme de survenue reste incompris. L'exploration des systèmes de neurotransmission et des voies métaboliques pourrait permettre d'élucider ces mécanismes. Les travaux effectués au cours de cette thèse se positionnent dans une optique de développement d'un outil de diagnostic précoce et de compréhension des mécanismes physiopathologiques grâce à l'imagerie TEP. Dans une première partie, nous avons caractérisé et validé un modèle murin de synucléinopathies. Nous avons conclu que le [18F]BF227 ne pouvait être employé comme radiotraceur des agrégats d'α-syn. La seconde partie a permis la mise au point d'une technique d'évaluation de l'affinité de molécules pour une cible donnée. Douze ligands froids ont pu être testés in vitro. Actuellement, aucun composé ne semble présenter les critères pour être un radiotraceur idéal. Enfin, la dernière partie a mis en évidence un hypométabolisme glucidique ainsi qu'une surexpression des récepteurs 5-HT1A à un stade précoce de la pathologie. Au final, cette étude a montré l'intérêt et les limites de l'imagerie TEP et des modèles animaux pour le développement d'un nouveau radiotraceur ainsi que pour l'exploration des mécanismes physiopathologiques / Neurodegenerative diseases are a major public health issue. Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are part of a family related to the pathological accumulation of a protein, α-synuclein (α- syn), and called synucleinopathies. To date, there is no pre-mortem formal diagnosis method for these diseases and the final confirmation only relies on postmortem studies. While the occurrence mechanisms remain unclear, exploration of neurotransmitter systems and metabolic pathways could bring more information on the underlying pathophysiological processes. The aims of this PhD work were (1) to develop the first radioligand targeting α-syn as an early diagnostic tool and (2) to investigate, with PET imaging, how neurotransmitter systems relates to pathophysiological mechanisms in an accelerated mouse model of synucleinopathy. In the first part of this study, we demonstrated the inability of in vivo PET imaging with [18F]BF227 to label α-syn aggregates in a model of synucleinopathy. The second part allowed the development of a competitive radioligand binding assay to determine α-syn binding parameters of non-radioactive candidate molecules. Twelve ligands were tested in vitro. Currently, no compound appears to present ideal α-syn binding properties. The last part of this study highlighted a serotoninergic hypometabolism and the overexpression of 5-HT1A receptors at an early stage of the disease in the synucleinopathy mouse model. Finally, this study demonstrated the advantages and limitations of PET imaging and animal models for the development of radiotracer and for the exploration of pathophysiological mechanisms

Vascularized composite allotransplantation has developed as a specialty at the interface of reconstructive and transplant surgery, offering restoration of function and form in scenarios where options for autologous reconstruction are limited, and for which the burden of donor-site morbidity may be high. Over the past 15 years some 28 patients have received face, and 85 patients upper extremity transplants. Results have been encouraging, with good functional outcomes, and the majority of patients reporting return to independence, employment and improved quality of life. However, the immunological management of these patients remains a significant challenge. While conventional immunosuppressive regimens have proven effective in preventing graft loss to rejection, they have failed to protect patients from acute rejection episodes, which have been reported in 85% during the first year post-transplant. When considered alongside the burden of comorbidity associated with life-long immunosuppression, the impetus for development of novel approaches to the prevention of rejection is clear. Induction of hematopoietic mixed chimerism has successfully achieved transplant tolerance, defined as specific unresponsiveness to donor antigens permitting life-long acceptance of transplanted tissues without maintenance immunosuppression, in numerous animal models and recently, of renal allografts in clinical trials. The work presented in this thesis investigates mixed chimerism for induction of tolerance of vascularized composite allografts (VCAs) across class I and II major histocompatibility (MHC) barriers in the Massachusetts General Hospital miniature swine model; a large animal model with defined MHC immunogenetics, and skin closely analogous to that of humans. The data presented demonstrate development of a reproducible model of VCA tolerance and stable hematopoietic mixed chimerism in a preclinical model. Importantly, tolerance extended to all components of VCAs including the epidermis and dermis, a previously un-reproducible finding. In vitro analysis demonstrated no evidence for either IL-2 reversible anergy or cellular regulation as mechanisms of donor-specific unresponsiveness, suggesting that at a systemic level, tolerance in this model may be primarily mediated by clonal deletion. In contrast, characterization of the cutaneous immune system demonstrated rapid infiltration of VCAs with recipient T cells and Langerhans’ cells, which in chimeric recipients did not cause rejection but rather established stable chimerism in all tissue-resident populations including dermal T cells with the phenotype of Tregs (CD25+FoxP3+); findings which suggest tissue-specific, and regulatory, mechanisms may play important roles. These data support the hypothesis that mixed chimerism is sufficient for whole-skin tolerance of VCAs, but further work is required to demonstrate the necessity of stable, rather than transient, chimerism and to confirm the necessity of other systemic or tissue-specific factors for prevention of epidermal rejection.

The sinus node (SN) is the natural pacemaker of the heart. In the human, the SN is surrounded by the paranodal area (PNA), the function of which is currently unknown. The PNA may act as subsidiary atrial pacemakers (SAP) and become the dominant pacemaker during sinus node dysfunction (SND). Creation of an animal model of SND allows characterisation of SAP, which can be a target for novel treatment strategies other than the currently available electronic pacemakers. I developed a large animal model of SND by ablating the SN in the goat and validated it by mapping the location of the newly emergent SAP. Functional characterisation of the SAP revealed reduced atrioventricular (AV) conduction time consistent with a location of the SAP close to the AV junction. SAP recovery time showed an initially significant prolongation compared to the SN recovery time, followed by a gradual decrease over 4 weeks. SAP pauses, and temporary reliance on electronic pacemaker activity have also been demonstrated then disappeared over time, suggesting possible modulation, maturation of the SAP. Structural characterisation of the SN revealed an extensive pacemaking complex within the right atrium (RA); the SN was surrounded by the PNA, extending down to the inferior vena cava (IVC) and into the interatrial groove. The PNA had a histological appearance that is intermediate to the SN and the RA. 3D reconstruction demonstrated, for the first time in a large animal model, an extensive and almost complete circle of pacemaking tissue at the junction of the embryologically different sinus venosus and the muscular right atrium. The SAP emerged in a location close to the IVC along the crista terminalis. Expression of key ion channel proteins in the SAP showed abundance of the pacemaker channel (HCN4) and the sodium/calcium exchanger (NCX1) compared to RA, similar to the expression pattern of the SN. The expression of the main high conductance connexin (Cx43) was not significantly different between SAP and RA, and both expressed Cx43 more abundantly than the SN.Conclusion: Destruction of the sinus node in this experimental model resulted in the generation of chronic SAP activity in the majority of the animals. The SAP displayed maturation over time and located in the inferior part of the RA, in the same area where the PNA was found in controls, suggesting the role of PNA as the dominant pacemaker in sinus node dysfunction. The SAP in the goat constitutes a promising stable target for electrophysiological modification to construct a fully functioning biological pacemaker.

L’addiction à la cocaïne, aussi appelée dépendance (APA 1994), est un trouble chronique associé à un risque élevé de rechute. Ce trouble touche une fraction significative des consommateurs de cocaïne (environ 15%) et est caractérisé par (1) une compulsion de la recherche et de la prise de cocaïne, (2) une perte de la capacité de contrôler sa consommation et (3) l’émergence d’un état émotionnel négatif (par exemple anxiété, irritabilité) lorsque le sujet dépendant est sevré. Le plus surprenant dans l’addiction est que les sujets atteints semblent agir contre leur propre intérêt, et ce malgré la conscience des conséquences néfastes de leur comportement. Un des grands enjeux actuels de la recherche sur l’addiction est de comprendre les mécanismes neurobiologiques expliquant le passage d’une consommation de drogue occasionnelle, récréative à une consommation compulsive et incontrôlée.Devant les limitations inhérentes aux études neurobiologiques chez l’homme (impossibilité d’utiliser des techniques invasives, méthodes employées corrélationnelles), ces études sont souvent complémentées par des études parallèles sur des modèles animaux de prise de drogue et d’addiction. Bien qu’ayant permis des découvertes importantes sur la neurobiologie de la cocaïne (comme par exemple l’implication du système dopaminergique dans les propriétés renforçantes de la cocaïne), la validité de ces modèles reste toutefois incertaine, en particulier à cause de l’absence de choix pendant l’accès aux drogues. Dans ces conditions, il est difficile de savoir si les animaux consomment de la drogue par compulsion ou bien par défaut d’autres choix.Afin d’étudier ce problème, nous avons développé dans notre équipe en 2007 un nouveau modèle dans lequel des rats ont le choix de prendre de la cocaïne ou de s’engager dans une autre activité récompensante (par exemple boire de l’eau sucrée avec de la saccharine). Il a ainsi pu être montré que la vaste majorité des animaux se détournaient de la drogue au profit de la récompense alternative. Mon travail de thèse a consisté à confirmer et tester la généralité et la robustesse de cette découverte surprenante. J’ai ainsi pu montrer que la cocaïne occupait une faible place sur l’échelle de valeur du rat, au niveau des concentrations les plus faibles d’eau sucrée. J’ai également pu établir que la préférence des animaux pour l’eau sucrée ne peut être expliquée ni par l’existence de propriétés anxiogènes de la cocaïne, ni par l’attrait pour la nouveauté du goût sucré et, enfin, ni par l’impossibilité de l’animal de contrôler son degré d’intoxication à la drogue. Enfin, de manière importante, j’ai pu constater que seule une minorité d’individus, n’excédant pas 15 % au niveau le plus sévère d’exposition à la drogue, continue à prendre de la cocaïne malgré le choix, même lorsqu’ils sont en privation alimentaire et qu’ils ont la possibilité de choisir un sucre naturel qui pourrait combler leur besoin en calories.L’ensemble de ces résultats pourrait alors signifier que, comme chez l’être humain, l’addiction à la cocaïne ne touche qu’une fraction minoritaire d’individus, la large majorité restante étant résiliente à l’addiction (c’est-à-dire résistante quelque soit le degré d’exposition à la cocaïne). Le modèle de choix pourrait donc servir à révéler et à sélectionner objectivement et efficacement les individus vulnérables face à l’addiction. Les nombreuses applications de cette méthode de sélection par le choix sont discutés à la fin de ma thèse / Drug addiction is defined as compulsive drug use that is, excessive and difficult to control despite negative consequences. A critical problem in current addiction research is to understand the transition between controlled and compulsive drug use. In standard drug self-administration settings, animals have no choice than drug use. As a result, serious doubt exists about the interpretation of drug use in experimental animals. Is it symptomatic of an underlying addiction state or merely an expectable response to lack of choice? This incertitude in turn casts a shadow over many behavioral and neurobiological changes that have been well documented in animals following extended drug self-administration. Do they reflect pathological dysfunctions or normal neurobiological adaptations?To address this issue, we have recently developed in our lab a rat model of the transition to cocaine addiction was recently developed and partially validated. Overall, available evidence shows that when a valuable behavioral option, even a biologically or physiologically inessential one, is made available during access to cocaine self-administration, most rats readily abstain from cocaine use in favor of the alternative reward regardless of the amount of past cocaine use. The goal of my thesis was to continue the validation of this model. My main results demonstrate that cocaine is very low on the value ladder of rats, and that this can't be explained away neither by the anxiogenic properties of cocaine, neither by saccharin habituation or satiation nor by the impossibility of the animals to control their cocaine intoxication. Overall, only a small minority of rats continue to self-administer the drug despite the opportunity of making a different choice. This pattern of results (i.e., abstinence in most rats; cocaine preference in few rats) maps well onto what is currently known about the epidemiology of human cocaine addiction. It is thus possible that the minority of cocaine-preferring rats would be homologous to the minority of human cocaine users with a diagnosis of addiction while the remaining majority of abstinent rats would be resilient to cocaine addiction. Choice could represent an objective method of selection of addicted animals for future research on the neurobiological dysfunctions that are hypothesized to underlie cocaine addiction. Other competing interpretations of the same pattern of results are also discussed at the end of this thesis

INTRODUÇÃO: Evidencia experimental sugere que padrões alterados de fluxo vascular, associados às bifurcações, estão envolvidos no desenvolvimento de lesões aneurismáticas. Pesquisamos os efeitos que a sobrecarga hemodinâmica condiciona sobre a parede arterial do ápice da bifurcação aórtica de modelos murinos. MÉTODOS: Sessenta ratos Wistar, selecionados e designados mediante amostragem probabilística simples foram agrupados equitativamente em um grupo controle e três grupos experimentais. Os espécimes foram anestesiados e sob magnificação microscópica, foi realizada uma incisão abdominal média e a aorta e os vasos ilíacos abordados e isolados desde a porção infra-renal até a porção distal da bifurcação. Modificação da geometria da bifurcação aórtica foi realizada mediante tunelamento da porção distal da artéria ilíaca no músculo ílio-lombar, no nível da raiz do membro inferior nos grupos II e IV. Nefrectomia esquerda e ligação da artéria renal inferior direita foram completadas para reforçar o estresse hemodinâmico nos grupos III e IV. Os modelos mantiveram-se em condições de laboratório convencionais com dieta standard para a espécie e água ad libitum para os grupos I e II e solução de NaCl 0,9% para os grupos III e IV. Após seis meses de seguimento, a bifurcação aórtica e as artérias ilíacas foram inspecionadas e subseqüentemente removidas para sua análise histopatológica. Um espécime por cada grupo foi submetido à angiografia digital com reconstrução tridimensional da bifurcação aórtica. RESULTADOS: 1) A pressão arterial, a freqüência cardíaca e a pressão de pulso entre os grupos, com e sem nefrectomia, mostraram diferenças com significância estatística (p <0,05). Os espécimes reunidos nos grupos III e IV que receberam sobrecarga de sódio desenvolveram um padrão hemodinâmico caracterizado por incremento da freqüência cardíaca e da pressão de pulso. 2) Seis espécimes (60%) do grupo IV desenvolveram aneurismas do ápice da bifurcação aórtica. 3) A avaliação angiográfica demonstrou que a morfologia da bifurcação do grupo controle se mantém sem modificações aparentes durante o período de seguimento. Entretanto, o grupo II apresenta dados de remodelamento longitudinal com tortuosidade e alongamento do tronco e ramos que conformam a bifurcação. Já o grupo III apresenta estenose proximal e dilatação incipiente da região do ápice da bifurcação em um padrão descrito como blister-like. Finalmente, o grupo IV demonstra aneurismas e estenoses múltiplas da porção proximal e distal ao divisor de fluxo. CONCLUSÕES: Em modelos murinos, deformações da geometria arterial, introduzidas por mudanças do ângulo de bifurcação, induzem a formação de aneurismas e a associação com hipertensão arterial, pressão de pulso aumentada, freqüência cardíaca elevada e sobrecarga de sódio potencializam a dilatação sacular desses segmentos / BACKGROUND: Experimental evidence indicates that altered patterns of vascular flow associated with bifurcations are involved in the development of aneurysmatic lesions. The effects of the hemodynamic overload on the arterial wall of the aortic bifurcation in murine models were studied. METHODS: Sixty Wistar rats were selected and assigned by simple random sampling into a control group and three experimental groups. The specimens were anesthetized. Under microscopic magnification an abdominal incision was performed and the aortic and iliac vessels were isolated from the infra-renal portion until the distal bifurcation. The modification of the geometry of the aortic bifurcation was accomplished by tunneling of the distal iliac artery into ilio-lumbar muscle in groups II and IV. Left nephrectomy and ligation of inferior right renal artery were completed to enhance the hemodynamic stress in groups III and IV. The models were maintained in conventional laboratory conditions with standard diet for the species and water ad libitum for groups I and II, and NaCl 0.9% for groups III and IV. After six months of follow up, the aortic bifurcation and iliac arteries were inspected and subsequently removed to its histopathological evaluation. One specimen from each group underwent angiography with digital three-dimensional reconstruction of the aortic bifurcation prior to sacrifice. RESULTS: 1) Blood pressure, heart rate and pulse pressure between the groups with and without nephrectomy showed statistically significant differences (p <0.05). The specimens collected in groups III and IV who received sodium overload developed a hemodynamic pattern characterized by increased heart rate and pulse pressure. 2) Six specimens (60%) in group IV developed aneurysmatic dilatation of the apex of the aortic bifurcation. 3) The angiographic evaluation showed that the morphology of the bifurcation of the control group remains unchanged during the study period. However, group II presents data from longitudinal remodeling with tortuosity and lengthening of the trunk and branches that make up the fork. The Group III presents stenosis and proximal dilatation of the apex of the bifurcation in a pattern described as blister-like. Finally, Group IV shows multiple stenosis proximal and distal to the flow divider. CONCLUSIONS: In murine models, the geometry deformation introduced by changes in the angle of bifurcation, induce inflammation of the flow divider, whereas, high blood pressure, pulse pressure, heart rate and high sodium overload catalyze the aneurysmatic dilatation of these segments