The Formula SAE is a student based competition organised by SAE International where engineering students from a university design, develop and test a formula-style race car prototype to compete against other universities. The competition car needs to satisfy the competition rules set out by the organisers. The competition strives to stimulate original, creative problem solving together with innovative engineering design practices. In any race environment, the primary goal is always to be as competitive as possible. Due to the competitive nature of motor sport, vehicle components need to withstand various and severe stresses. The components of a race car vehicle are responsible for the vehicle’s handling characteristics and reliability. The chassis is a crucial and integral component of a Formula SAE competition car, primarily responsible for the vehicle’s performance characteristics. The chassis is the structural component that accommodates all the other components. A Formula SAE chassis is a structure that requires high torsional stiffness, low weight as well as the necessary strength properties. In this study, multiple Formula SAE chassis were designed and developed using computer aided design software. Each concept’s torsional stiffness, weight and strength properties were tested using finite element analysis software. The different concepts consisted of different design techniques and applications. All the concepts were analysed and assessed, leading to the identification of an acceptable prototype. The prototype was manufactured for experimental tests. The designed chassis complied with the Formula SAE rules and regulations. The weight, torsional stiffness and strength characteristics of the designed chassis frame were also favourable compared to accepted standards for Formula SAE chassis frames. The manufactured chassis was prepared for experimental tests in order to validate the simulation results produced by the finite element analysis. The torsional stiffness, weight and strength were experimentally determined and the results were compared with the corresponding simulations results. The comparison of the experimental and simulated results enabled the validation of the finite element analysis software. The study draws conclusions about the use of computer aided design and finite element analysis software as a design tool for the development of a Formula SAE chassis. Closure about the study is provided with general conclusions, recommendations and research possibilities for future studies. / MIng (Mechanical Engineering), North-West University, Potchefstroom Campus, 2014

Background: Thoracic aortic aneurysms and dissections (TAAD) have a genetic component with an estimated 20-25% of the patients having a positive family history. An aneurysm often precedes a dissection. Acute aortic dissections are associated with high mortality and morbidity, even when operated on. Complications due to prophylactic surgery are considerably fewer. Therefore, patients at risk for dissection should be identified, followed-up and evaluated for prophylactic intervention. Aims: 1. To establish reference values for ascending (AoA) and descending aortic (AoD) diameters measured by computed tomography. 2. To study the effectiveness of phenotypic cascade screening in families with an inherited form of thoracic aortic aneurysms and dissections (FTAAD) and to address questions that arise when screening for a genetic disorder is applied. 3. To study the agreement of aortic diameters obtained by TTE and MRI and to study aortic stiffness in individuals from families with FTAAD. 4. To perform exome sequencing in order to identify pathogenic sequence variants causing FTAAD, to characterize the phenotype, and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers. Results: Paper I: The diameter of the thoracic aorta increased by 0.17 mm (0.12 – 0.20 mm) per year. The mean sex-related difference in diameter was 1.99 mm (1.28 – 2.60 mm) with men having larger aortas than women. The mean difference in aortic diameter per unit BMI was 0.27 mm (0.14 – 0.44 mm). Upper normal limits for the AoA can be calculated by the formula D (mm)=31+0.16*age and for the AoD by D (mm)=21+0.16*age. Paper II: Of 106 individuals from families with FTAAD but without known thoracic aortic disease, 19 individuals (18%) were identified to have a dilated AoA. The expected number of individuals in this group with an autosomal dominant disease would have been 40 (p<0.0001). In first-degree relatives younger than 40, we found only one individual with a dilated aorta although the expected number of individuals with disease causing mutation would have been 10. Paper III: Of 116 individuals investigated, 21 were identified with thoracic aortic dilatation and 95 individuals with normal thoracic aortic diameter. Aortic stiffness increased with age and diameter. The individuals with aortic dilatation were older than those without (49 vs. 37 years, p=0.001) and showed lower aortic elastic properties. The diameters measured by TTE and MRI correlated strongly (r2=0.93). The mean difference in diameters between the two methods was 0.72 mm (95% CI 0.41-1.02) with TTE giving larger diameters than MRI. Paper IV: From exome sequencing and segregation analysis, a 2-bp deletion in the MYLK gene (c.3272_3273del) was identified to cause FTAAD. The age and the aortic diameter at dissection or rupture varied in the family members. We did not find any differences in aortic diameter, aortic stiffness, or pulse wave velocity between carriers and non-carriers. Conclusions: Thoracic aortic diameter increases with age, and sex and body size are also associated with the diameter. In FTAAD, screening identifies family members with a previously unknown aortic dilatation. However, a normal aortic diameter does not exclude an individual from being a carrier of FTAAD. TTE can be used in follow-up for the ascending aorta. Individuals identified to have a dilated thoracic aorta have increased aortic stiffness compared to individuals with normal thoracic aortic diameter. The MYLK mutation (c.3272_3273del) causes thoracic aortic dissections with variable clinical expression. No differences in aortic stiffness were identified between MYLK mutation carriers and non-carriers.

In vibration-based damage detection in structures, often changes in the dynamic properties such as natural frequencies, modeshapes, and derivatives of modeshapes are used to identify the damaged elements. If only a partial list of natural frequencies is known, optimization methods may need to be used to identify the damage. In this research, the algorithm proposed by Podlevskyi & Yaroshko (2013) is used to determine the stiffness distribution in shear building models. The lateral load resisting elements are presented as a single equivalent spring, and masses are lumped at floor levels. The proposed method calculates stiffness values directly, i.e., without optimization, from the known partial list of natural frequency data and mass distribution. It is shown that if the number of stories with reduced stiffness is smaller than the number of known natural frequencies, the stories with reduced stiffnesses can be identified. Numerical studies on building models with two stories and four stories are used to illustrate the solution method. Effect of error or noise in given natural frequencies on stiffness estimates and, conversely, sensitivity of natural frequencies to changes in stiffness are studied using 7-, 15-, 30-, and 50-story numerical models. From the studies, it is learnt that as the number of stories increases, the natural frequencies become less sensitive to stiffness changes. Additionally, eight laboratory experiments were conducted on a five-story aluminum structural model. Ten slender columns were used in each story of the specimen. Damage was simulated by removing columns in one, two, or three stories. The method can locate and quantify the damage in cases presented in the experimental studies. It is also applied to a 1/3 scaled 18-story steel moment frame building tested on an earthquake simulator (Suita et al., 2015) to identify the reduction in the stiffness due to fractures of beam flanges. Only the first two natural frequencies are used to determine the reductions in the stiffness since the third mode of the tower is torsional and no reasonable planar spring-mass model can be developed to present all of the translational modes. The method produced possible cases of the softening when the damage was assumed to occur at a single story.

Biomimetic tactile sensing was previously mostly performed in medical situations, such as when locating tumors in patients’ bodies. This thesis examined the effectiveness of using a biomimetic tactile sensory equipment for examining pressure distribution throughout carton board packages, made in two different carton board qualities. The purpose was to examine to what extent biomimetic tactile sensing was able to mimic the results of a group of human test subjects evaluations. Eight packages, made from two different materials, were tested. There were four packages of each of the materials. Each package had four points where displacement measurements with a force of 6N were conducted. The packages were then measured twice on a single point on the edge of the package, with the force of 12N.  The packages at disposal were compressed using a uniaxial-tensile-testing machine alongside with the aforementioned equipment. The pressure sensitive film was placed on top of the packages and a limit on the maximum force to be applied was set on the testing machine. Two limits on the applied forces were set, the first to see the distribution of pressure within the range of elastic deformation, so that no lasting deformation would have occurred. The second force limit was set to see the moment where the elastic deformation area transformed into the plastic deformation area, to see whether or not there was a difference in the distribution of pressure pre- or post-plastic deformation. From the results from compression tests, it was clear that there was a difference in pressure distribution before and after the plastic deformation had occurred. The experimental diagrams showed that the curves were vastly different in both cases. It was also clear that there was a significant difference in the distribution of pressure, depending on if the pressure was applied closer to the middle compared to closer to the center of the package (single vs multiple concentration of forces, respectively). Inspecting results from packages made in both carton board qualities, there were no clear results as the same trends could be seen throughout the tests.  It was concluded that the BioTac could be used to accurately identify concentrations of forces, differences in pressure distribution and the location of deformation. This means that the BioTac will be useful in future experiments, when objectively evaluating and defining grip stiffness, with the help of methods such as the finite-element method. / Biomimetiskt taktilt avkännande var något som tidigare mestadels utfördes för medicinala syften, såsom för att lokalisera tumörer i patienters kroppar. Detta examensarbete undersökte effektiviteten av att använda en biomimetisk taktil avkännare för att granska tryckfördelningen genom kartongförpackningar, gjorda av material från två olika kartongkvaliteter. Totalt åtta förpackningar, gjorda av två olika material, provades. Det var fyra av varje materialtyp. Varje förpackning mättes på fyra punkter med 6N och sedan två gånger på samma punkt med 12N. Förpackningarna till förfogande trycktes ihop med en enaxlad drag- och tryckprovare samt den tidigare nämnda avkännaren. En tryckkänslig film användes mellan avkännaren och förpackningen för att tydligt se tryckfördelningen på alla förpackningarna. Två gränser på den maximala tillåtna kraften upprättades i tryckmaskinen, 6N och 12N. Den lägre nivån sattes för att undersöka tryckfördelningen inom det elastiska deformationsområdet, utan att en kvarstående plastisk deformation uppstått. Den högre gränsen sattes för att undersöka skedet där det elastiska deformationsområdet övergår till det plastiska. Båda gränsvärdena valdes för att undersöka om det gick att urskilja en skillnad i tryckfördelningen innan och efter plastisk deformation, eller inte.  Från resultaten av dessa kompressionstest var det tydligt att det fanns en skillnad i tryckfördelning före och efter den plastiska deformationen uppstått. De uppställda diagrammen visade att kurvorna var mycket annorlunda i båda fallen. Det var, dessutom, relativt tydligt att det fanns en skillnad i tryckfördelning beroende av om trycket var applicerat närmre mitten av paketet jämfört med om det var applicerat närmre kanten av paketet (enskilda kraftkoncentrationer vid mitten av förpackningarna och multipla koncentrationer vid kanten av förpackningarna). Genom att undersöka resultat från förpackningar gjorda av båda kartongkvaliteter, upptäcktes ingen tydlig skillnad i förpackningarna, då liknande trender uppstod i båda materialen. Slutsatsen drogs att BioTac kunde användas för att finna kraftkoncentrationer, skillnader i tryckfördelning, samt området för deformation. Detta betyder att BioTac-sensorn kan vara nyttig vid framtida experiment, för att objektivt utvärdera och definiera greppstyvhet, med metoder som finita-element-metoden.

This thesis examines the bearing capacity, stiffness, shear and moment force of a continuous wooden beam and how the parameters of the beam changes when the beam is spliced ​​with nail plate. A literature study has been conducted to examine which studies have been carried out in this field. Construction timber is the most common wooden element for wooden constructions but has limitations in available lengths since the maximum length manufactured is 5400 mm. If larger lengths are required, splicing must occur or use of other materials.   The study examines a 2 series, a 3-point series (moment and shear) and a 4-point series (moment). Each series consists off 3 trials in each series to see how shear and moment force affect the strength. The study also shows which off the joints that gives the least strength. The samples are tested in a draw and pressure machine lying on 2 supports and with a point load for the 3-point method and 2-point loads for the 4-point method. In the trials pressure is applied until the beams break. The study investigates the lab results, fracture state and use state for the wooden beams being tested. The result of the study shows that a splicing will lower the wood's carrying capacity between 21-60% compared to a non-spliced beam for the 3-point method and a reduction of 40-66% compared to a non-spliced beam for the 4-point method. Despite the lowered bearing capacity all the experiments are still within the characteristic value and approved for use. A larger dimension on the nail plate would probably have given a better value. / Detta examensarbete undersöker bärförmåga, styvhet, moment- och tvärkrafts påverkan hos en kontinuerlig träbalk och hur parametrarna för balken ändras då balken skarvas med spikplåt. En litteraturstudie har genomförts för att undersöka vilka studier som utförts på området. Konstruktionsvirke är det vanligaste träelementet vid träkonstruktioner men har begränsningar i tillgängliga längder då maxlängden som tillverkas är 5400mm. Vid behov av större längder måste skarvning förekomma eller användning av andra material. I studien undersöks två serier, en 3-punktsserie (moment och tvärkraft) samt en 4-punktsserie (moment). Varje serie består av 3 försök för att se hur moment och tvärkraft påverkar hållfastheten. Studien visar även vilken typ av skarv som ger minst hållfasthet. Proverna testas i en drag-tryck-maskin liggandes på 2 upplag med 1 punktlast anbringad för 3-punktsmetoden och 2 punktlaster för 4-punktsmetoden. I försöken anbringas kraft på balkarna tills de går i brott. Studien undersöker labbvärdet, brottstadiet och bruksstadiet för balkarna som testas. Analysen av försöken visar att en skarvning kommer sänka balken bärförmåga med mellan 21–60% gentemot en ren träbalk för trepunktsmetoden och en minskning på mellan 40–66% gentemot en ren träbalk för fyrpunktsmetoden. Trots den sänkta bärförmågan för balken i testerna är alla försöken inom det karaktäristiska värdet och godkända att användas. En större dimension på spikplåten hade antagligen gett ett bättre värde.

Este trabalho apresenta um estudo sobre as estruturas metálicas espaciais abordando os seguintes aspectos: histórico e desenvolvimento, tipos, vantagens do sistema tridimensional e comportamento estrutural. Atenção especial é dispensada às tipologias de treliças espaciais mais comuns no Brasil, formadas por tubos circulares com variações de inércia nas extremidades. A influência da variação de inércia nas extremidades das barras no comportamento destes elementos isoladamente (resistência à compressão) e comportamento global da estrutura, foi estudada via elementos finitos. Descrevem-se vários sistemas de ligações patenteados utilizados em outros países e os comumente usados no Brasil. Apresentam-se resultados experimentais e teóricos de uma treliça espacial com dimensões em planta de 7,5 x 7,5 m. Na análise teórica foram considerados a variação de inércia nas barras e os efeitos da não linearidade geométrica. Analisou-se também, com as mesmas considerações anteriores, modelos de treliças espaciais de dimensões maiores que o modelo ensaiado. / This work presents a study of space steel structures including the following aspects: history and development, types, advantages of three-dimensional system and structural behaviour. It is given special attention to the most common types of space trusses in Brazil, composed of tubular sections bars with flattened ends. The influence of the variable stiffness on each element\'s behaviour (compressive strength) and on the global structural behaviour has been studied with the use of finite elements. Various patent connection systems used in other countries and those commonly used in Brazil are described. Experimental and theoretical results of a 7,5 m-long by 7,5 m-wide space truss are presented. In the theoretical analysis, variable stiffness and effects of geometrical non-linearity have been considered. Still applying the above considerations, larger space truss models have been also analysed.

A retificação é um dos processos mais utilizados em operações de acabamento, geralmente caracterizada pelo resultado dimensional atingido e baixas rugosidades. Apesar de seu uso intenso na indústria, há aspectos ainda desconhecidos do processo e de sua estabilidade, sendo considerados tempos excessivos de centelhamento para atingir boas condições dimensionais. Este trabalho propõe um novo modelo para determinar o menor tempo de centelhamento necessário para que as deformações do sistema máquina-rebolo-peça sejam absorvidas e a dimensão objetivo da peça alcançada. Esse modelo partiu do equacionamento descrito por S. Malkin para obtenção da rigidez da máquina e avançou na obtenção da constante característica do tempo τ de forma experimental. A comprovação do modelo proposto deu-se em dois experimentos, sendo o primeiro experimento aplicado para determinar o valor de τ em função da velocidade de avanço, segundo o modelo de Malkin. Comprovou-se que o τ varia, principalmente em baixas velocidades de avanço. O segundo experimento teve como objetivo determinar qual o menor tempo de centelhamento necessário para que as deformações do sistema máquina-rebolo-peça sejam plenamente absorvidas e compará-las com o modelo proposto. Os resultados teórico e experimental comprovaram que, para as velocidades de mergulho 3,0 e 2,5 mm/min, com τ = 0,219 e 0,204 s, respectivamente, o tempo mínimo de centelhamento de 1,0 s foi suficiente para absorver as deformações elásticas inseridas no sistema. De forma comparativa, o modelo proposto foi mais eficaz que o de Malkin para o cálculo do tempo de centelhamento e do erro diametral da peça para relações t1/τ menores ou iguais a 20, sendo t1 o tempo em segundos da fase de retificação em desbaste. Conclui-se que o modelo proposto neste trabalho mostrou-se eficiente para predizer o tempo mínimo necessário para centelhamento e a redução diametral da peça, considerando o valor experimental de τ. / Grinding is one of the processes most commonly used in finishing operations, usually characterized by good dimensional results and low roughness values. Despite the extensive use in industry, there are still unknown aspects of the grinding process and its stability, with excessive spark-out times being used to achieve good dimensional requirements. This research work proposed a new model to determine the shortest spark-out time required to absorb the machine-wheel-workpiece system deformations and to achieve the desired workpiece diameter. This model derived from the equation described by S. Malkin to obtain the machine stiffness and consisted in experimentally obtaining the time characteristic constant τ. The verification of the proposed model was done in two experiments. The first one was performed to determine the value of τ according to the radial infeed velocity (vf), as proposed by S. Malkin. It was shown that the τ varies, especially at low feed rates. The second objective was to determine the shortest spark-out time needed, in which all machine-wheel-workpiece system deformations were fully eliminated and to compare it to the one calculated by the proposed model. The theoretical and experimental results showed that for radial infeed velocities of 3.0 and 2.5 mm/min, with τ = 0.219 and 0.204 s, respectively, the spark-out time of 1 s was long enough to ensure that the elastic deformations introduced into the system were fully absorbed. Comparatively, the proposed model was more effective than the Malkin\'s one to predict the spark-out time and the diametric error for the ratio t1/τ lower that 20, being t1 the time in seconds for the rough grinding stage. As a conclusion, the proposed model proved to be effective in predicting the minimum spark-out time and the workpiece diameter reduction, when considering the experimental value of τ.

Introdução: As células do músculo liso vascular (CMLV) são quiescentes nos vasos adultos, com baixa capacidade de migração e de secreção de matriz extracelular, caracterizando fenótipo contrátil. Evidências apontam para a heterogeneidade fenotípica das CMLV ao longo da árvore arterial: há distribuição heterogênea de doenças e de resposta a determinadas drogas nos diferentes vasos, além de variabilidade de expressão dos genes de proteínas contráteis de músculo liso entre eles. O papel das CMLV, em fase adulta, é classicamente descrito como restrito à regulação do tônus de pequenos vasos, sendo insignificante a contribuição da mecânica das CMLV para a complacência das artérias elásticas. Existe a hipótese de que a viscoelasticidade das CMLV contribua para a mecânica final das artérias, sendo o enrijecimento dessas células associado à rigidez arterial. Objetivo: Estudar a variabilidade das propriedades mecânicas e de expressão proteica das CMLV, ao longo da árvore arterial, buscando identificar moduladores regionais para esse fenótipo. Avaliar se situações clínicas sabidamente associadas à rigidez arterial (envelhecimento, sexo feminino pós-menopausa, ancestralidade genética africana, diabetes mellitus e tabagismo) cursam com enrijecimento de CMLV. Métodos: 1) Estudou-se a composição e a organização da camada média de diferentes artérias. As CMLV desses vasos foram avaliadas quanto à viscoelasticidade de citoplasma (G), por meio do ensaio de Citometria Magnético Ótica de Oscilação e, quanto à expressão proteica global, usando cromatografia multidimensional e espectrometria de massas em tandem de alta resolução (Proteômica Shotgun). Os dados mecânicos obtidos foram correlacionados com as características da matriz extracelular (MEC) dos vasos de origem (porcentagem de elastina e quantidade de MEC). Em paralelo, foi realizado experimento de estiramento cíclico (10%/1Hz) das CMLV das diferentes artérias por 24 e 48h, seguido pela mensuração de rigidez de citoplasma. 2) Foram isoladas as CMLV de fragmentos de artéria mamária de 80 pacientes submetidos à cirurgia de revascularização do miocárdio, células essas que foram avaliadas quanto à viscoelasticidade de citoplasma (G, G\' e G\'\'). Elaborou-se modelo estatístico para avaliar se as variáveis clínicas idade, sexo feminino, ancestralidade africana, tabagismo e diabetes mellitus estavam associadas a alterações de mecânica celular. Resultados: 1) A viscoelasticidade das CMLV variou significativamente entre as artérias. As CMLV provenientes de artérias distais (artérias femoral e renal) mostraram-se significativamente mais rígidas que as CMLV de aorta torácica (p < 0,001). Identificou-se correlação negativa entre rigidez de CMLV e quantidade de MEC / elastina na camada média vascular. O regime de estiramento cíclico por 48h reduziu globalmente a rigidez das CMLV. As CMLV provenientes da aorta torácica expressaram maior quantidade de proteínas relacionadas com a estrutura e a organização do citoesqueleto em relação às CMLV da artéria femoral. 2) Constatou-se variabilidade interindividual de viscoelasticidade de CMLV e associação entre tabagismo e sexo feminino com enrijecimento de CMLV. Conclusões: As CMLV são heterogêneas quanto às propriedades mecânicas, à organização do citoesqueleto e à expressão proteica ao longo da árvore arterial, reforçando o conceito de plasticidade fenotípica das CMLV. A mecânica das CMLV é modulada pelas características da MEC e pela tensão circunferencial cíclica aplicada às paredes vasculares pelo fluxo sanguíneo. Mulheres pós-menopausa e tabagistas exibem enrijecimento de CMLV, sendo esse fato um provável contribuinte para a rigidez arterial associada a essas condições e um possível alvo terapêutico a ser avaliado futuramente / Rational: Vascular smooth muscle cells (VSMC) lose their ability to migrate and secrete extracellular matrix (ECM) with the end of vascular development, condition known as contractile phenotype and reversible in the presence of vascular injury. There is evidence of heterogeneity of VSMC phenotype along arterial tree, as the distribution of diseases (atherosclerosis) and the response to drugs vary between different vessels, as well as the expression of smooth muscle-contractile protein genes. The role played by VSMC mechanics on determining large arteries\' compliance was always considered irrelevant. It has been hypothesized that the VSMC mechanical properties are important for vascular mechanics, especially in the pathological scenario, where VSMC stiffening may be associated with arterial rigidity. Goals: Study the variation of VSMC mechanics and protein expression along arterial tree, identifying regional modulators of this phenotype. Evaluate if clinical situations associated with arterial rigidity (ageing, post-menopausal women, African ancestry, diabetes mellitus and smoking) concur with VSMC stiffening. Methods: 1) Different arteries were studied in terms of composition and organization of their media layer. VSMC isolated from these arteries were evaluated regarding cytoplasm viscoelasticity, measured using Optical Magnetic Twisting Cytometry Assay (OMTC), and protein expression, using two-dimensional liquid chromatography and tandem mass spectrometry (Shotgun Proteomics). Mechanical data were correlated with ECM characteristics (percentage of elastin and ECM amount) of the vessels of origin. In parallel, VSMC of different arteries were subjected to cyclic stretching (10%/1Hz) during 24 and 48h, followed by the measurement of their cytoplasm rigidity. 2) VSMC were isolated from fragments of mammary artery of 80 patients subjected to coronary bypass surgery and evaluated regarding their viscoelasticity (G, G\' e G\'\'). A statistic model was elaborated to address if the clinical variables age, female sex, African ancestry, smoking and diabetes mellitus were associated with changes of VSMC mechanics. Results: 1) VSMC viscoelasticity varied significantly amongst the studied arteries. VSMC from heart-distant arteries (femoral and renal arteries) were stiffer than VSMC from thoracic aorta (p < 0,001). There was a negative correlation between VSMC rigidity and the amount of ECM / percentage of elastin within the media layer. 48h-cyclic stretching was associated with a global reduction of VSMC rigidity. VSMC of thoracic aorta expressed significantly more proteins associated with cytoskeleton structure and organization than VSMC of femoral artery. 2) There was a significant inter-individual variation of VSMC viscoelasticity. Smoking and female sex were associated with VSMC stiffening. Conclusion: VSMC mechanics, cytoskeleton organization and protein expression are heterogeneous along arterial tree. VSMC mechanical properties are modulated by ECM characteristics and by regional mechanical forces. This reinforces the concept of phenotypic heterogeneity of VSMC. Post-menopausal women and smokers exhibit stiffer VSMC, representing an important factor for the understanding of the arterial rigidity associated with these conditions and also a possible future therapeutic target

Les conséquences cardiovasculaires du vieillissement sont l'une des principales causes de mortalité. En plus de l'âge chronologique, plusieurs autres facteurs peuvent influencer l'apparition des modifications liées au vieillissement. L'étude des déterminants génétiques et environnementaux accélérateurs du vieillissement cardiovasculaire pourrait améliorer la prévention de ces pathologies. Nous avons démontré chez le rat Zucker (modèle de syndrome métabolique) en fin de vie (80 semaines) que l'obésité et les troubles métaboliques associés et le vieillissement agissent de façon synergique pour modifier la structure et la fonction vasculaire, en ciblant les propriétés endothéliales. L'augmentation précoce des acides gras libres (AGL) plasmatiques et les altérations de réactivité carotidienne qu'ils induisent sont des mécanismes clés du développement de la rigidité artérielle dans ce modèle. La souris déficiente pour le gène Klotho (Kl) possède une faible espérance de vie, un vieillissement accéléré et des pathologies semblables à celles de l'homme âgé. Nous avons caractérisé le phénotype artériel (peu connu) des souris Kl+/- à 6 et 12 mois, en comparaison de leurs contrôles Kl+/+ aux mêmes âges. Nous avons démontré dans ce modèle que dans des conditions basales, les souris Kl+/- ne présentent pas de phénotype de vieillissement accéléré de la paroi artérielle à l'âge de 12 mois. Néanmoins, à l'âge de 6 mois, les souris Kl+/- présentent une augmentation de leur rigidité carotidienne, en faveur d'une altération de la fonction vasculaire. L'étude de ces deux modèles nous a ainsi permis d'évaluer l'implication de l'obésité et de la protéine Klotho dans le vieillissement artériel / The cardiovascular consequences of aging are a leading cause of death. In addition to chronological age, several other factors may influence the onset of changes associated with aging. The study of genetic and environmental determinants of cardiovascular aging accelerators could improve prevention of these diseases. We have demonstrated in very old (80 weeks) Zucker rats (model of metabolic syndrome) that obesity and associated metabolic disorders act synergistically with aging to alter the vascular structure and function by targeting endothelial properties. The early increase in plasma free fatty acids (FFA) and alterations in carotid responsiveness induced by AGL are key mechanisms of development of arterial stiffness in this model. Mouse deficient for the gene Klotho (Kl) has a short life expectancy, accelerated aging and diseases similar to an old man. We characterized the arterial phenotype (unknown) mice Kl +/- at 6 and 12 months, compared to their controls K +/+ at the same ages. We have demonstrated in this model that in basal conditions, Kl +/- mice show no phenotype of an accelerated aging of the arterial wall at the age of 12 months. However, at the age of 6 months, mice Kl +/- show an increase in carotid stiffness in favor of an alteration of vascular function. The study of these two models has allowed us to assess the implication of obesity and Klotho protein in aging arteries

Ce projet traite de la programmation développementale de l'hypertension artérielle (HTA) à travers des influences néonatales précoces pouvant moduler le développement vasculaire. Les bébés prématurés présentent des défenses antioxydantes diminuées comparés aux nouveau-nés à terme et sont exposés à la naissance à des concentrations élevées en oxygène (O2) engendrant la production d'espèces réactives de l'O2 (ERO). Les conséquences vasculaires à long terme de dommages liés aux ERO en période néonatale et les mécanismes impliqués sont très partiellement compris. Les précédents résultats du laboratoire ont montré qu'un stress hyperoxique néonatal conduit chez le rat adulte à de l'HTA, une dysfonction endothéliale et une rigidité artérielle, éléments de vieillissement vasculaire. Nous émettons l'hypothèse qu'un stress hyperoxique néonatale conduit à long terme à l'altération de la structure vasculaire et à un vieillissement vasculaire précoce. Nous avons démontré une diminution de la prolifération cellulaire, une capacité angiogénique altérée, des dommages à l'ADN et une augmentation de l'expression de protéines de sénescences (des indices de sénescence cellulaire) au-delà de la période néonatale suite à une exposition brève à l'O2 au niveau vasculaire dans un modèle animal (ratons Sprague-Dawley exposés à 80 % d'O2 du 3ème au 10ème jour de vie comparés à des ratons restés à l'air ambiant) et cellulaire (cellules musculaires lisses d'aortes thoraciques d'embryon de rat exposées à 40% O2 pendant 24h ou 48h, puis remises en normoxie pendant 96h). De plus, des altérations des composants de la structure vasculaire indiquant un remodelage vasculaire aortique ont été mises en évidence. Ces changements précèdent tous l'HTA et la dysfonction vasculaire observées dans le modèle animal à l'âge adulte et pourraient y contribuer. L'étude de jeunes adultes nés < 29 semaines comparés à des jeunes adultes nés à terme indique une augmentation de marqueurs de rigidité artérielle (indices d'un vieillissement vasculaire précoce) chez la population prématurée. L'ensemble des résultats démontre un vieillissement vasculaire précoce après une exposition néonatale transitoire à un stress hyperoxique permettant une meilleure compréhension des mécanismes physiopathologiques impliqués dans la survenue des troubles vasculaires retrouvés chez l'adulte et contribue à la mise en place de moyens de prévention chez des patients prématurés / The scope of this thesis is developmental programming of arterial high blood pressure (HBP) hypertension through early neonatal stimuli that may alter vascular development. Premature newborns have decreased antioxidant defenses compared to term babies and are exposed upon birth to high oxygen (O2) concentration, causing reactive oxygen species (ROS) production. Long term vascular consequences of ROS related damage during the neonatal period and the mechanisms involved remain unknown. Recent data from the laboratory show that neonatal hyperoxic stress leads in adult rat to HBP, endothelial dysfunction and arterial rigidity, characteristic features of vascular aging. We hypothesize that a neonatal hyperoxic stress leads to long term vascular structure alteration explained by an early aging of the vascular system. We showed a decreased proliferation rate, an altered angiogenic capacity, as well as long term DNA damage and increased expression of senescence proteins at a vascular level following O2 exposure in the animal (male Sprague-Dawley pups kept at 80% O2 from postnatal days 3 to 10 vs. rats remained in room air) and cellular models (embryonic vascular smooth muscle cells from rat thoracic aorta exposed to 40% O2 for 24h or 48h followed by 96h recovery in control conditions). In addition, alterations of vascular structure components indicating vascular remodeling was shown before the onset of the HBP at adult age. Those changes precede the HBP and vascular dysfunction observed in our animal model at adult age and could contribute to them. Study of young adults born before 29 weeks vs. young adults born at term showed that young adults born preterm present indices of arterial stiffness vs. term controls. Results of the present thesis demonstrate a major role of premature vascular aging in the surge of vascular diseases in adulthood and contribute to a better understanding of the patho-physiological mechanisms involved and could put into practice new prevention strategies among preterm patients