In this thesis the nature and strengthening effect of the various precipitates in Al-4% Cu are reviewed, followed by a literature survey on the response of this alloy to fatigue. The first experiments described were carried out to measure the Bauschinger effect and the results of these are presented. The experimental study was further extended by cyclic straining corresponding to fatigue conditions and the results obtained are presented graphically and through electron micrographs. The fatigue behaviour was further investigated at liquid air temperature. Also, the effect of heat treatments carried out during the interruption of fatigue on a specimen containing metastable θ" precipitates is reported. All the experiments were carried out on single crystals and most of them with 112 orientation as indicated later. / Thesis / Master of Science (MS)

Field-based liquefaction evaluation procedures include the stress-based, strain-based, and energybased based approaches. The existence of a volumetric threshold shear strain, γtv, under which there is no development of excess pore pressures, and the unique relationship between pore pressure ratio and cyclic shear strain, γc, make a compelling argument for using a strain-based approach. However, the cyclic strain approach has not yet been standardized for field evaluations. The primary objective of this thesis is to use published databases of 415 shear-wave velocity and 230 Standard Penetration Test liquefaction field case histories to investigate the performance of the cyclic strain approach for the evaluation of initial liquefaction relative to the cyclic stress approach. Additionally, the concept of the γtv is expressed in terms of the peak ground surface acceleration and defined as the threshold amax. Computing (amax)t could provide a fast and simple evaluation for initial liquefaction, where no liquefaction is expected for a minimum computed (amax)t determined from the case histories. The variant of the strain-based procedure proposed herein avoids the direct need for laboratory cyclic testing by employing pore pressure generation models that are functions of cyclic shear strain, number of equivalent cycles, and relative density to predict initial liquefaction. The results from the proposed procedure are compared with those of the stress-based approach to determine which better matches the field observations of the case histories. It was found that the cyclic strain approach resulted in 70% to 77% correct predictions. In contrast, the cyclic stress approach yielded 87% to 90% correct predictions. The reasons why the predictions were not always correct with the cyclic strain approach are due to inherent limitations of the cyclic strain approach. Most significantly, an inherent and potentially fatal limitation of the strain-based procedure is it ignoring the softening of the soil stiffness due to excess pore pressure in representing the earthquake loading in terms of γc and neqγ. / Master of Science / Earthquakes can cause heavy damage when they occur. One of the ways in which this happens is when the earthquake shaking causes the soil to behave like a liquid. This is the phenomenon known as liquefaction. An example of liquefaction is a person sinking in quicksand. Relating this to earthquakes, liquefaction can be thought of as a building sinking in quicksand that formed as a consequence of earthquake shaking. Destructive cases of liquefaction have been reported in almost all major earthquakes. When cases of liquefaction are properly documented, they can provide information that will help engineers and scientists assess the efficacy of existing liquefaction evaluation procedures and/or to develop new procedures. There are different methods to evaluate the occurrence of liquefaction, with the cyclic stress approach being the most widely used. This study assesses the efficacy of an alternative approach to see if it yields better predictions of liquefaction triggering than the cyclic stress approach. The approach under consideration is called the cyclic strain approach. To examine the effectiveness of the cyclic strain approach, sites that experienced liquefaction in the past were analyzed to see if the predictions made with the approach matched the past field observations. Due to potential shortcomings in implementing the strain based procedure, as well as inherent limitations of the procedure, the strain-based procedure yielded predictions that were inferior to the more widely used stress-based procedure.

Les anévrysmes se développant au niveau des fistules artério-veineuses (FAV), représentent une complication rare mais potentiellement mortelle dont la physiopathologie reste inexplorée. Jusqu’à présent la pratique courante était de les remplacer par un segment prothétique. Nous avons proposé un nouveau traitement chirurgical consistant en une anévrysmorraphie veineuse renforcée extérieurement par une exoprothèse. Notre premier objectif a été de rapporter les résultats à un an de cette nouvelle technique. Dans un second temps nous avons perfusé ex vivo des veines saphènes humaines renforcées par la même exoprothèse dans des conditions hémodynamiques de shear stress (SS) artériel en faisant varier la pression. L’analyse morphologique a montré le développement d’une hyperplasie intimale dans la veine sans et avec exoprothèse à haute pression. L’analyse des gènes et des protéines impliqués dans le remodelage vasculaire n’a pas montré de différence entre la veine nue et la veine renforcée mais nous a permis de mieux caractériser le rôle du SS et de la pression dans le mécanisme de l’artérialisation veineuse. Notre troisième objectif a été de décrire le remodelage anévrysmal des FAV. A partir d’une tissuthèque constituée d’échantillons de veines prélevées chez les patients opérés, nous avons comparé la veine artérialisée anévrysmale à la veine non artérialisée non anévrysmale. Les métalloprotéinases et leurs inhibiteurs participent activement à ce remodelage. Les anévrysmes régulièrement ponctionnés ont un profil inflammatoire qui influence la nature de ce remodelage. / Aneurysm complicating arteriovenous fistula (AVF) is a rare but potentially life-threatening complication. To date, its pathobiology remains unexplored and prosthetic replacement constitutes the conventionnal treatment. We have proposed a new surgical technique consisting in a venous aneurysmorraphy reinforced by an exoprosthesis. Our first goal was to evaluate the one-year results in terms of patency and aneurysm recurrence. Secondly, we have studied the impact of the exoprosthesis on human saphenous veins perfused ex vivo and submitted to different flow conditions consisting in an arterial shear stress (SS) in association with a low or a high pressure setting. Morphological analysis revealed an intimal hyperplasia in veins with and without exoprosthesis under high pressure. Analysis of the proteins and genes involved in the vascular remodeling did not showed an exoprosthesis effect but allowed us to better decipher the selective role played by SS and pressure in the arterialization process. Thirdly, we have collected tissue samples from patients operated and compared aneurysmal arterialized veins to non-aneurysmal non-arterialized veins. Metalloproteinases and their inhibitors actively participate in the remodeling. In aneurysms frequently cannulated inflammation influence the remodeling process.

Heart failure, predominately caused by myocardial infarction (MI), is the leading cause of death in the United States. Currently the only treatment for heart failure is cardiac transplantation, but studies show that progenitor cell, biomaterial, or combined therapies have improved cardiac function post-MI. The endogenous environment of CPCs is drastically different from commonly used culture conditions. Further the endogenous environment changes with age and disease state. We evaluated the behavior of CPCs cultured on a naturally-derived, cardiac extracellular matrix (cECM) as compared to the standard culture coating collagen I, that also mimics fibrotic tissue. In this study, CPCs cultured on cECM had improved cell numbers and cardiomyogenic maturation. However, the microenvironmental cues responsible for stimulating CPC activation are largely unknown. During development, aging and disease the myocardium changes in matrix composition and stiffness exposing endogenous cells to a wide variety of stimuli. In a combinatorial study, we evaluated the effect of cyclic strain and extracellular matrix composition on CPC behavior. The response of CPCs to signals from the microenvironment is complex, with more matrix-dependency observed at lower strains. Alignment, cell division and paracrine signaling are extracellular matrix and strain dependent. Extracellular matrix conditions affect CPC maturation and calcium signaling. Mechanotransduction pathways, including focal adhesion kinase and extracellular signal-regulated kinase, are activated through adhesion and maintained under cyclic strain. Insights from this work will advance pragmatic cell therapy attempts to regenerate healthy myocardium post-MI.

A stretchable silver ink was screen printed to TPU sheets, then tensile coupons of the TPU, both bare and laminated to cotton, Denim and spandex fabric, were subjected to 1000 cycles of 20% uniaxial strain. In-situ resistance measurements of printed traces were processed to generate datasets of maximum and minimum resistance per cycle. A mechanistic fit model was used to predict the resistance behavior of the ink across TPU/fabric levels. The results show that traces strained on TPU laminated to spandex (polyester) fibers had an average rate of increase in resistance significantly lower than that of traces strained on bare TPU. The variation in predicted resistance was significantly lower in the spandex group than in the TPU group. Trace width was not found to have a significant effect on the resistance behavior across TPU/fabric groups. More testing is required to understand the effect of lamination to high elasticity fabrics on resistance behavior as it relates to the viscoelastic properties of the fibers and weave structure.

The soil strata is often subjected to various kinds of vibrations such as that caused by earthquakes, water waves, traffic loads, wind power plants, construction related equipments, pile driving and vibratory machines. The strains induced in a soil mass due to the vibrations generated by these different sources often lie in a range of 0.0001% - 0.1%. The estimation of the shear modulus (G) and damping (D) of soils in this strain range becomes an important aspect for performing the analysis and design of various geotechnical structures subjected to different kinds of vibrations. Strain amplitude, effective confining stress, void ratio/relative density, number of vibration cycles and cyclic strain history are some of the key parameters that influence the modulus and damping characteristics of sands. Although, the effects of strain amplitude, confining pressure and relative density have been studied quite extensively in literature, only limited studies seem to have been reported in literature to examine the effects of the cyclic strain history and the vibration cycles on these dynamic properties. The objective of this thesis is to study the effects of the cyclic strain history and the number of vibration cycles on the shear modulus and damping ratio of dry sands in a strain range of 0.0001% to 0.1%. A number of resonant column tests have been performed on dry sand specimens to examine the effect of the cyclic shear strain history, by including both increasing and decreasing strain paths, on the shear modulus and damping ratio for different combinations of relative densities (Dr) and confining pressures (σ3); an increasing strain path intends to simulate a situation when a vibratory machine is just started before reaching a steady state of vibration, and on the other hand, the decreasing strain path matches a condition when the machine is shut down after running continuously in a steady state for some time. The specimen has been subjected to a series of cycles of increasing and decreasing shear strain paths approximately in a shear strain range of 0.0006% - 0.1%. For chosen values of relative density and confining pressure, two different series of tests beginning with either (i) an increasing strain path or (ii) a decreasing strain path, were performed. In addition, the influence of the numbers of the vibration cycles which are used to measure the resonant frequency of the specimen, referred to as the cycle constant, on the values of shear modulus has also been analyzed. Irrespective of the strain path adopted to commence the test or the cycle constant used to perform a resonant column test, for a given strain amplitude, the shear modulus along the increasing strain path has been found to be always greater than the corresponding modulus value along the decreasing strain path. For the series of tests which were commenced with the increasing strain path, the shear modulus corresponding to the first increasing strain path becomes always the highest as compared to the subsequent strain paths. For a given strain cycle, irrespective of relative density of sand, the difference between the values of G associated with the increasing and decreasing strain paths becomes always the maximum corresponding to a certain shear strain level. The maximum reduction in the shear modulus, due to the cyclic variation of the shear strain, was noted to be approximately one fourth of the maximum shear modulus (G0). This reduction in the shear modulus, on account of the cyclic variation of the shear strain, increases generally with decrease in the values of both relative density and confining pressure. The damping ratio for a given shear strain for the increasing strain path was noted to be lower than the corresponding value for the decreasing strain path except for the first increasing strain path. For a particular strain level, the series of tests started with the decreasing strain path resulted in a lower value of shear modulus for all the cyclic strain paths as compared to the tests which were commenced with the increasing strain path. The modulus reduction curve for the first increasing strain path was noted to be more or less the same irrespective of the value of the chosen cycle constant. For the subsequent strain paths, an increment in the cycle constant value caused a reduction in the shear modulus at a particular shear strain level. In order to match a situation when the machine is running continuously in a steady state of vibration, resonant column tests were conducted in a torsional mode by inducing a large number of the vibration cycles with the shear strain amplitude in a range of 0.0005%-0.05%. Corresponding to a given input voltage of the drive mechanism, the specimens were subjected to a number of vibration cycles ranging from 1,000 to 50,000. The values of shear modulus and damping ratio, before and after the application of vibration cycles, were determined for several input voltages ranging from 0.001 V (minimum) to 0.3 V (maximum). The tests were carried out for different combinations of relative densities and confining pressures. For the chosen relative densities, hardly any influence of vibration cycles on the values of G and D were noted for the strain amplitude below the threshold strain level (0.0024% - 0.0044%). Beyond the threshold strain level, an induction of the vibration cycles leads to a continuous increment in the shear strain which eventually causes (i) a decrease in the shear modulus, and (ii) an increase in the damping ratio. This effect was found to become especially more significant for lower values of relative densities as well as confining pressures. The percentage changes in the values of (i) shear strain, (ii) shear modulus, and (iii) damping ratios after the introduction of vibration cycles were noted to increase with an increment in the number of vibration cycles. However, for a given increment of the vibration cycles, the changes in the values of shear modulus and damping ratio were generally noted to subside with an increase in the number of the vibration cycles. At various strain levels, the magnitude of the shear modulus was observed to increase continuously with an increase in the values of both relative density and confining pressure. For the shear strain greater than the threshold strain (0.0024% - 0.0044%), a reduction in the damping ratio values was also noted with an increase in the magnitudes of the confining pressure. On the other hand, the influence of relative density on the damping ratio was found to be relatively negligible. The shear modulus reduction curves from the present tests' data were found to compare reasonably well with the empirical curves proposed in the literature, especially for low values of the confining pressure. A deviation of the present modulus reduction curves from the empirical curves was observed generally at large shearing strains. However, the damping values obtained from the present study were noted to be lower than the values predicted by the existing empirical correlations, particularly for low values of the confining pressure. An attempt has also been made to improve the accuracy of the measurement of the arrival times of both primary (P) waves and shear (S) waves while conducting bender/extender element tests. For this purpose, a series of laboratory tests were performed on dry sand at different frequencies, varying between 1 kHz and 10 kHz, for medium dense and very dense sands with different values of the confining pressures. While determining the times of arrival of both P and S waves, two corrections have been proposed to incorporate (i) the presence of an initial offset in the input signal, and (ii) the time lag due to an existence of peripheral electronics between the input and received signals when the source and receiver elements are kept in direct contact with each other. The absolute magnitude of the resultant of these two corrections was found to reduce with an increase in the frequency of the input signal. The determination of the P-wave arrival time does not pose much difficulty. It has been noted that it becomes equally accurate to measure the arrival times of the S-wave provided the proposed corrections are incorporated. The maximum shear modulus values measured from the resonant column tests and the bender element tests by incorporating these two corrections were found to compare reasonably well with each other. The thesis brings out the effects of the cyclic strain history and the vibration cycles on the shear modulus and damping ratio of dry sand. The results obtained are expected to be useful while doing the analysis and design of geotechnical structures subjected to different kinds of vibrations.

An injured vascular system has a substantial impact on an individuals overall health, and an understanding of the mechanisms that underlie blood vessel pathophysiology is required for the development of rational and effective treatment strategies. The phenotypic modulation of smooth muscle cells (SMC) during vascular injury, characterized by altered adhesion, migration and synthetic behavior, plays an important role in the eventual outcome. Specifically, the ability of SMCs to adhere to and remodel their extracellular environment via regulation of the syndecan class of cell adhesion molecules dictates the response of the vascular wall to local injury. The effect of in vitro syndecan-4 regulation on SMC adhesion was investigated through the use of a glass microsphere centrifugation assay, and an antisense-mediated reduction in gene expression was found to correlate with decreased adhesive strength. Regulation of syndecan-1, syndecan-2, and syndecan-4 gene expression was observed experimentally by mechanical strain of SMCs. Using real-time polymerase chain reaction (PCR), the kinetics of both static and cyclic mechanical strain were found to modify the gene expression in a time and strain magnitude-dependent manner unique to each syndecan. In particular, the responses of syndecan-4 were acute, but transient, while the evolution of syndecan-1 and syndecan-2 regulation was delayed by comparison. Mechanical strain also modulated syndecan-4 protein expression and ectodomain shedding, as measured by Western immunoblotting, and this effect was found, through selective inhibition, to be at least in part dependent on mitogen-activated protein (MAP) kinase signaling. In particular, intact extracellular signal-regulated MAP kinase (ERK) 1/2 and c-Jun NH2-terminal kinase / stress-activated protein kinase (JNK/SAPK) signaling pathways were found to be required for the observed strain-induced shedding. These findings offer a better understanding of syndecan function in response to mechanical strain and suggest potential new mechanisms by which physical forces may modulate vascular SMC behavior and regulation during normal physiology, pathologic conditions, and engineered arterial substitute development.

Mg-Druckgusslegierungen sind aufgrund ihrer geringen Dichte potenzielle Leichtbauwerkstoffe. Ihre Festigkeitseigenschaften werden durch erhöhte Temperatur und die druckgussprozessbedingte Porosität maßgeblich beeinflusst. Zur Auslegung zyklisch belasteter Mg-Druckgussbauteile für eine begrenzte Betriebsdauer kann das Örtliche Konzept verwendet werden. Im Örtlichen Konzept nimmt das zyklische Werkstoffverhalten eine zentrale Rolle ein. Es umfasst das zyklische Verformungsverhalten und das zyklische Ermüdungsverhalten. Zur Beschreibung des zyklischen Werkstoffverhaltens werden die zyklische Spannungs-Dehnungs-Kurve für das Verformungsverhalten und die Dehnungswöhlerlinie für das Ermüdungsverhalten verwendet. Ziel der vorliegenden Arbeit ist es, die Einflüsse Temperatur und Porosität auf das zyklische Werkstoffverhalten der Mg-Druckgusslegierungen AZ91 und AM50 quantitativ zu erfassen. Dazu wird ein objektives Regressionsverfahren ermittelt, mit dem die zyklische Spannungs-Dehnungs-Kurve und die Dehnungs-Wöhler-Linie gemeinsam unter Einhaltung der Kompatibilitätsbedingungen aus den Daten einer Versuchsreihe regressiert werden können. Desweiteren wird eine Methodik entwickelt, mit der Ansätze zur quantitativen Erfassung von Einflüssen auf das zyklische Werkstoffverhalten aus Versuchsdaten abgeleitet werden können. Diese Methodik wird zur Untersuchung der Einflüsse Temperatur und Porosität auf das zyklische Werkstoffverhalten der Mg-Druckgusslegierungen AZ91 und AM50 angewendet. Die Untersuchungsergebnisse und deren Validierungen werden in dieser Arbeit vorgestellt. / Die-cast magnesium alloys are potential light-weight materials due to their low density. Their mechanical properties are significantly affected by elevated temperatures and by porosity, which die castings are especially prone to. The local strain approach can be used for dimensioning cyclically loaded magnesium die castings for a limited service life. The central role of this approach is assigned to the cyclic material behaviour. The cyclic material behaviour includes the cyclic deformation behaviour and the cyclic fatigue behaviour. It is characterized by the stress-strain curve for the cyclic deformation behaviour and by the strain-life curve for the cyclic fatigue behaviour. In the present work the aim is to describe the influence of elevated temperatures and of porosity on the cyclic material behaviour quantitatively. Therefore, a method is developed, which allows an objective and combined regression of the stress-strain curve and the strain-life curve for one test series. Furthermore, a methodology is developed, for deriving a formulation from experimental data to describe an arbitrary influence on the cyclic material behaviour quantitatively. This methodology is used to study the influences of elevated temperature and of porosity on the cyclic material behaviour of the die-cast magnesium alloys AZ91 and AM50. The results of the investigations and their validation are presented in this treatise.

Mg-Druckgusslegierungen sind aufgrund ihrer geringen Dichte potenzielle Leichtbauwerkstoffe. Ihre Festigkeitseigenschaften werden durch erhöhte Temperatur und die druckgussprozessbedingte Porosität maßgeblich beeinflusst. Zur Auslegung zyklisch belasteter Mg-Druckgussbauteile für eine begrenzte Betriebsdauer kann das Örtliche Konzept verwendet werden. Im Örtlichen Konzept nimmt das zyklische Werkstoffverhalten eine zentrale Rolle ein. Es umfasst das zyklische Verformungsverhalten und das zyklische Ermüdungsverhalten. Zur Beschreibung des zyklischen Werkstoffverhaltens werden die zyklische Spannungs-Dehnungs-Kurve für das Verformungsverhalten und die Dehnungswöhlerlinie für das Ermüdungsverhalten verwendet. Ziel der vorliegenden Arbeit ist es, die Einflüsse Temperatur und Porosität auf das zyklische Werkstoffverhalten der Mg-Druckgusslegierungen AZ91 und AM50 quantitativ zu erfassen. Dazu wird ein objektives Regressionsverfahren ermittelt, mit dem die zyklische Spannungs-Dehnungs-Kurve und die Dehnungs-Wöhler-Linie gemeinsam unter Einhaltung der Kompatibilitätsbedingungen aus den Daten einer Versuchsreihe regressiert werden können. Desweiteren wird eine Methodik entwickelt, mit der Ansätze zur quantitativen Erfassung von Einflüssen auf das zyklische Werkstoffverhalten aus Versuchsdaten abgeleitet werden können. Diese Methodik wird zur Untersuchung der Einflüsse Temperatur und Porosität auf das zyklische Werkstoffverhalten der Mg-Druckgusslegierungen AZ91 und AM50 angewendet. Die Untersuchungsergebnisse und deren Validierungen werden in dieser Arbeit vorgestellt. / Die-cast magnesium alloys are potential light-weight materials due to their low density. Their mechanical properties are significantly affected by elevated temperatures and by porosity, which die castings are especially prone to. The local strain approach can be used for dimensioning cyclically loaded magnesium die castings for a limited service life. The central role of this approach is assigned to the cyclic material behaviour. The cyclic material behaviour includes the cyclic deformation behaviour and the cyclic fatigue behaviour. It is characterized by the stress-strain curve for the cyclic deformation behaviour and by the strain-life curve for the cyclic fatigue behaviour. In the present work the aim is to describe the influence of elevated temperatures and of porosity on the cyclic material behaviour quantitatively. Therefore, a method is developed, which allows an objective and combined regression of the stress-strain curve and the strain-life curve for one test series. Furthermore, a methodology is developed, for deriving a formulation from experimental data to describe an arbitrary influence on the cyclic material behaviour quantitatively. This methodology is used to study the influences of elevated temperature and of porosity on the cyclic material behaviour of the die-cast magnesium alloys AZ91 and AM50. The results of the investigations and their validation are presented in this treatise.

Erkrankungen des Herz-Kreislaufsystems sind trotz erheblicher Fortschritte in Diagnostik und Therapie noch immer die häufigste Todesursache in Deutschland. Neben bekannte Risikofaktoren wie Hypercholesterinämie, Hyperlipoproteinämie, Diabetes mellitus, Adipositas, Bewegungsmangel, Stress und hohem Alter wird eine pathophysiologisch erhöhte Bildung reaktiver Sauerstoffspezies (ROS) als Ursache für deren Entstehung diskutiert. NAD(P)H-Oxidasen, von denen 7 Isoformen der katalytischen Nox-Untereinheiten bekannt sind, stellen dabei die Hauptquelle für vaskuläre Superoxidanionen und oxidativen Stress dar. In dieser Arbeit konnte die vorrangige Bedeutung eines intrazellulär lokalisierten Nox4-haltigen NAD(P)H-Oxidase-Komplexes für die konstitutive Radikalbildung in primären humanen Endothelzellen nachgewiesen werden. Weiterhin konnte gezeigt werden, dass durch chronische Applikation der biomechanischen Kräfte Schubspannung und Dehnung oxidativer Stress in humanen Endothelzellen in vitro vermindert werden kann. Die Herabregulation der Superoxidanionen-Bildung sowie die vermehrte Freisetzung von NO durch chronische Applikation biomechanischer Kräfte trägt zur positiven Balance von NO/Superoxidanionen und zum vasoprotektiven Potential physiologischer Schubspannung bzw. Dehnung bei. Durch Nox4-Promotordeletionsanalysen und Mutationsstudien konnte der Transkriptionsfaktor AP-1 als entscheidend für die schubspannungsabhängige Herabregulation von Nox4 identifiziert werden. Durch Stimulation von Endothelzellen bzw. murinen Gefäßringen mit oxidiertem LDL konnte dagegen die vaskuläre ROS-Bildung in vitro und ex vivo induziert werden. Zur weiteren Aufklärung des Mechanismus der LDL-induzierten ROS-Bildung in vivo und des Einflusses von NAD(P)H-Oxidasen wurden C57BL/6 (Wildtyp)- und Nox2-/--Mäuse 10 Wochen lang mit einer fettreichen Diät (Western diet) gefüttert und anschließend der Einfluss dieser Fütterung auf die NAD(P)H-Oxidase-Expression und ROS-Bildung analysiert. In der Aorta thoracalis beider Mausstämme zeigte sich durch das fettreiche Futter ein signifikanter Anstieg der NAD(P)H-Oxidase-Aktivität im Vergleich zum Standardfutter. Durch Western diet-Fütterung wurde die Nox4-mRNA-Expression in der A. thoracalis von Nox2-/--Mäuse und die p22phox-mRNA-Expression in beiden Mausstämmen induziert. Die Analyse weiterer Organe (Herz, Niere) zeigte keine Induktion von NAD(P)H-Oxidase-Untereinheiten durch Western diet-Fütterung. Zusammenfassend sprechen die Ergebnisse der vorliegenden Arbeit für eine entscheidende Rolle der Nox4-haltigen NAD(P)H-Oxidase bei der vaskulären Radikalbildung in vitro und in vivo. / Cardiovascular diseases are the most common causes of death in Germany. Beside the known risk factors hypercholesteremia, hyperlipoproteinemia, diabetes mellitus, obesity, sedentary lifestyle, stress and high age, a pathophysiologically increased formation of reactive oxygen species (ROS) are discussed as cause of development of cardiovascular diseases. Nicotine adenine dinucleotide phosphate (NADPH) oxidase complexes have been identified as main source of oxidative stress and vascular superoxide anions. There are 7 known isoforms of the catalytic Nox subunit of the NADPH oxidase. In this dissertation it was shown that NADPH oxidase subunit Nox4 is the major Nox isoform in human endothelial cells. Nox4 could be localized in the perinuclear space. Overexpression of Nox4 enhanced endothelial superoxide anion formation. Furthermore, a reduction of oxidative stress could be demonstrated by chronic application of the biomechanical forces laminar shear stress and cyclic strain in endothelial cells in vitro. The observed downregulation of superoxide anion formation and upregulation of NO formation by application of biomechanical forces contribute to the positive balance between NO and superoxide anion and the vasoprotective potential of physiological shear stress and cyclic strain. Molecular cloning and functional analysis of the human Nox4 promoter revealed that an AP-1 binding site is essential for downregulation of Nox4 by laminar shear stress. On the other hand stimulation of endothelial cells and murine vessels with oxidized lipids caused an upregulation of vascular ROS production in vitro and ex vivo. In order to examine the mechanism of LDL induced ROS formation and the influence of NADPH oxidase, C57BL/6 (wild-type) and Nox2-/- mice were feed with a diet high in fat and sugar (Western-type diet) for 10 weeks. After feeding, the influence of diet on the expression of NADPH oxidase and ROS production was analyzed in the A. thoracalis. Both mice strains showed a significant upregulation of aortic ROS production in comparison to normal chow. The mRNA expression of aortic Nox4 was induced in Nox2-/- mice. Furthermore, the aortic p22phox mRNA expression was upregulated in both mice strains. The analysis of other organs (heart, kidney) showed no influence of the Western-type diet. In conclusion, the results demonstrate a major role of a Nox4 containing NADPH oxidase in the vascular radical formation in vitro and in vivo.