Veronica Gambillara
Hemodynamics have crucial role in the control of vascular tone, in the regulation of arterial remodeling, and in the production of mediators that maintain arterial function. Changes in hemodynamics forces induce profound alterations in vascular cell metabolism and function, in the extracellular matrix, and in smooth muscle cell (SMC) phenotypes, all being part of vessel wall remodeling. Vessel wall remodeling plays a key role in arterial wall homeostasis but also in the initiation and development of arterial disease. This aim of this work is to study the effects of two distinct biomechanical stimuli, oscillatory shear and cyclic stretch on vessel wall function. Our 71 investigation is performed using an improved in vitro artery perfusion system, which allows to study the exact contribution of each biomechanical stimulus on isolated arterial segments, where the biological cell responses of endothelial and SMCs, and the extracellular matrix interactions are well preserved. The present thesis is divided into two main sections. The first part focuses on the effects of oscillatory shear stress on arterial segments, a mechanism presumed to be involved in the localization and initiation of atherosclerotic plaques. The second section investigates the influence of reduced cyclic stretch on the arterial wall, a procedure that is occurring in arterial stiffening. In the first and second papers, we examined the effects of three different shear stress conditions on the endothelium, SMC, and arterial wall responses, in porcine carotid arteries perfused in vitro for three days. We demonstrated that oscillatory shear stress, which is usually present in plaque-prone areas, decreased the bradykinin-induced vasorelaxation after 3 days of perfusion. The endothelial dysfunction was correlated to an impaired endothelial nitric oxide synthase gene expression and bradykinin-mediated activation. The potential lack of nitric oxide production and/or bioavailability observed in arteries exposed to oscillatory shear stress may also be the cause of the start of matrix turnover. Expression and activation of matrix metalloproteinase-2 and-9 were increased in arteries exposed to oscillatory shear, suggesting that this type of shear stress triggers a remodeling process. This part of the study provides a new insights on the role of shear stress in the control of arterial function and supports the hypothesis that oscillatory shear stress is a determining factor predisposing the arterial wall to atherosclerosis. The third paper focuses on the effects of cyclic stretch on vascular smooth muscle function, phenotype and wall remodeling. Arteries were wrapped by an external banding, which drastically decreased compliance and therefore the cyclic stretch. Arteries were perfused for one day under a unidirectional shear stress (6±3 dyn/cm2) in combination with a mean pressure of 80 mmHg and a pulse pressure of +/-10 mmHg. We demonstrated that exposure to reduced cyclic stretch induced a rapid modulation of SMC phenotype which was combined with a decrease in norepinephrine-induced vasocontraction. SMC dedifferentiation was associated to a decrease of plasminogen activator inhibitor-1 expression, which, combined with enhanced matrix metalloproteinase-2, may promote wall remodeling and SMC migration. These findings give a further approach into possible consequences of an arterial stiffening on large vessel wall patho-physiology.
EPFL2005
