Arterial in vitro remodeling:analysis of biomechanical and biological factors influencing the adaptive response

Vascular remodeling is defined as any enduring change in the size and composition of an adult blood vessel, allowing adaptation or repair. The vascular remodeling response has been shown to depend on a variety of endogenous and environmental factors. Physiological remodeling is a tightly regulated process that mainly occurs in response to long-term changes in hemodynamic conditions. The adaptation to these hemodynamic changes implies the production of mediators that influence structure as well as function. A loss of regulation in the adaptive response underlies the pathogenesis of major cardiovascular diseases, including hypertension, atherosclerosis, restenosis and arterial aneurismal dilatation. Specialized enzymes called matrix metalloproteinases (MMPs) have been shown to have a predominant participation in the reorganization of the vessel structure, through the degradation of the extracellular matrix scaffold. The aim of this thesis is to gain insight in the biological and mechanical processes taking place in the vascular wall as an adaptive response to different biomechanical stimuli such as blood pressure and blood flow. This work proposes a new model for the study of vascular remodeling where physical factors acting on the arterial wall can be dissociated and analyzed, individually, in relation to the biological response. The results are presented in form of an introduction, three scientific papers and a conclusion section. The investigation has been designed around three different approaches: adaptation of a non-uniform artery to an in vitro environment, vascular adaptation to steady and pulsatile pressure and vascular adaptation to unidirectional and oscillatory flow. The adaptive response to each one of the variables chosen has been analyzed through biological and biomechanical remodeling indicators of the arterial wall. The introduction is an overview of the biological and biomechanical characteristics of arterial wall in relation to the remodeling process. The contribution of vascular smooth muscle cells and extracellular matrix to physiological and pathological arterial remodeling is discussed. Paper I assesses the relative remodeling of a non-axisymmetric artery in relation to its environment. The study considers the native circumferential asymmetry of the porcine right common carotid, which results from the non-homogenous mechanical and hemodynamic native environment. The adaptive response of the artery to an in vitro perfusion environment is analyzed. The study shows that in vitro perfusion leads, through remodeling, to a circumferentially uniform scleroprotein distribution and to a change in arterial compliance. This study emphasizes the link between structural changes, the biomechanical response and the enzymatic implication in the adaptive response. In paper II we investigate the role of continuous and cyclic stretch, produced by steady or pulsatile pressure acting on the arterial wall, on the remodeling response. The study shows that exposure to continuous and cyclic stretch differentially affects the relative scleroprotein content and leads to a change in arterial wall stiffness. The adaptive outcome is studied through an integrative approach taking into consideration the geometrical and structural adaptation, the biomechanical behavior and the enzymatic agents implicated in extracellular matrix turnover. Paper III analyzes the influence of different flow patterns on the arterial adaptive response. We investigate the differential effects of oscillatory flow, mimicking a plaque-prone hemodynamic environment, and unidirectional flow, to mimicking a physiologically protective (plaquefree) environment. The effect of these hemodynamic forces on the remodeling response are characterized through the study of endothelial and smooth muscle cell function as well as through assessment of agents influencing extracellular matrix turnover. The conclusions section presents a synthesis of the results and contribution of this thesis and proposes perspectives for future studies

Governance, priorities and policies in national research for health systems in West Africa (Guinea Bissau, Liberia, Mali, Sierra Leone)

Contributions to the content of this paper through interviews, presentations and mapping exercises were made by country teams present at the March 2011 Dakar workshopWorkshop objectives (2011) identified shared problems that could be tackled through collective strategies, and action plans to be tailored to each country (Guinea Bissau, Liberia, Mali and Sierra Leone). Goals for research for health (R4H) system strengthening were identified as priority areas for development in the four countries. The papers provide a descriptive review of key elements of the national health research systems in each country, and present a cross-country comparison, highlighting similarities and differences in country needs and challenges with respect to R4H system development

Health Research Web and research capacity mapping

PowerPoint presentationHealth Research Web (HRWeb) is an interactive platform for Health Research and Health Research Systems. The presentation shows users how to navigate the HRWeb platform, the kinds of search results it provides, and how to expand search functions using document references. A drop-down menu includes country categories and links to Governance and Policies; National Priorities for Health Research; Key Institutions/Networks; Regulation and Ethics Review; Research Financing and Partnerships; Health Research Projects and Publications; and Information Resources. See https://www.healthresearchweb.org

Biomechanical adaptation of porcine carotid vascular smooth muscle to hypo and hypertension in vitro

Previous research in arterial remodeling in response to changes in blood pressure seldom included both hyper- and hypotension. To compare the effects of low and high pressure on arterial remodeling and vascular smooth muscle tone and performance, we have utilized an in vitro model. Porcine carotid arteries were cultured for 3 days at 30 and 170mmHg and compared to controls cultured at 100mmHg for 1 and 3 days. On the first and last day of culture, pressure-diameter and pressure-wall thickness curves were measured under normal smooth muscle tone using a high-resolution ultrasonic device. Last-day experiments included measurements where vascular smooth muscle was contracted or totally relaxed. From the data wall cross-sectional area, Hudetz elastic modulus and a contraction index related to the diameter reduction under normal smooth muscle tone were calculated. We found that although wall cross-sectional area (indicating wall mass) did not change much, Hudetz elastic modulus was significantly reduced in the 3-day hypotension group. Inspection of the wall contraction index suggests that this is due to a reduction in the vascular smooth muscle tone. Further, the peak of contraction index was found to be shifted to higher pressures in the 3-day 170mmHg group. We conclude that vascular smooth muscle performance adapts to both hypo- and hypertension at short time scales and can alter the biomechanics of the vascular wall in vitro

Functional, mechanical and geometrical adaptation of the arterial wall of a non-axisymmetric artery in vitro

Vascular remodeling is an adaptive response to variations in the hemodynamic environment acting on the arterial wall. Remodeling translates into changes of structure, geometry and mechanical properties of the artery. Our aim was to study the remodeling response of pig right common carotid arteries in vitro

Arterial wall response to ex vivo exposure to oscillatory shear stress

The aim of this study was to analyze the arterial wall response to plaque-prone hemodynamic environments, known to occur mainly in areas of arterial trees such as bifurcations and branching points. In these areas, the vasculature is exposed to cyclically reversing flow that induces an endothelial dysfunction predisposing thus arteries to local development of atherosclerotic plaques

Agendas de investigación priorizadas: un recurso estratégico para la salud en América Latina

OBJETIVO: Conocer y analizar los procedimientos de elaboración de las agendas nacionales de investigación integradas entre 2007 y 2011 en Argentina, Guatemala, México, Panamá y Paraguay. MÉTODOS: Estudio descriptivo y transversal utilizando una encuesta administrada vía internet a los participantes en la elaboración de las agendas, sobre los procesos de desarrollo, integración, instrumentación y utilización y difusión de la agenda. RESULTADOS: Los 45 participantes comunicaron haber seguido metodologías específicas para la construcción de las agendas y consideraron como buenos los aspectos organizativos en cuanto a la información previa aportada y el equilibrio entre las disciplinas y los actores clave. El 60% consideró imparciales a los coordinadores, aunque 25% señaló sesgos que favorecían algún tema. El 42% recibió apoyo técnico de consultores, lecturas y guías metodológicas. El 40% reportó haber realizado la priorización de temas. El 55% señaló haber constatado la diseminación y comunicación de la agenda, pero solo 22% comunicó la inclusión de temas de las agendas desarrolladas en convocatorias nacionales de investigación. CONCLUSIONES: El desarrollo de las agendas de investigación para la salud en los países estudiados se caracterizó por la planificación previa y la organización adecuada para lograr resultados consensuados. No obstante, las agendas no se utilizaron en las convocatorias nacionales, lo que refleja la falta de coordinación en los Sistemas Nacionales de Investigación para la Salud y la desconexión entre los financiadores y los investigadores. Se recomienda fortalecer el trabajo de integración y abogacía de actores clave para lograr modificar los procesos y estructuras de las convocatorias de investigación basadas en las agendas desarrolladas

Plaque-prone hemodynamics impair endothelial function in pig carotid arteries

Hemodynamic forces play an active role in vascular pathologies, particularly in relation to the localization of atherosclerotic lesions. It has been established that low shear stress combined with cyclic reversal of flow direction (oscillatory shear stress) affects the endothelial cells and may lead to an initiation of plaque development. The aim of the study was to analyze the effect of hemodynamic conditions in arterial segments perfused in vitro in the absence of other stimuli. Left common porcine carotid segments were mounted into an ex vivo arterial support system and perfused for 3 days under unidirectional high and low shear stress (6 +/- 3 and 0.3 +/- 0.1 dyn/cm(2)) and oscillatory shear stress (0.3 +/- 3 dyn/cm(2)). Bradykinin-induced vasorelaxation was drastically decreased in arteries exposed to oscillatory shear stress compared with unidirectional shear stress. Impaired nitric oxide-mediated vasodilation was correlated to changes in both endothelial nitric oxide synthase (eNOS) gene expression and activation in response to bradykinin treatment. This study determined the flow-mediated effects on native tissue perfused with physiologically relevant flows and supports the hypothesis that oscillatory shear stress is a determinant factor in early stages of atherosclerosis. Indeed, oscillatory shear stress induces an endothelial dysfunction, whereas unidirectional shear stress preserves the function of endothelial cells. Endothelial dysfunction is directly mediated by a downregulation of eNOS gene expression and activation; consequently, a decrease of nitric oxide production and/or bioavailability occurs