Shear stress and the regulation of vascular function and structure

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Our arteries are lined by a single layer of cells called the vascular endothelium. Due to their position on the inside of the artery, the endothelial cells are constantly exposed to the frictional force created by the flowing blood. Termed shear stress, this frictional force plays a key role in regulating endothelial cell responses that change artery size and stiffness in both the short and the long term. We are interested in understanding the sensitivity of the endothelium to changes in shear stress, the speed of its responses and how these factors may differ in arteries that are in the arms vs. the legs. We will use cutting edge Doppler ultrasound technology to non-invasively measure changes in shear stress and changes in artery function, size, wall thickness and stiffness. In daily living, the most common cause of increases in shear stress is performing exercise. Regular exercise also results in long term changes in artery function and structure, however, we do not know the extent to which these changes are brought about by increases in shear stress per se, or other variables that are altered by exercise. We will isolate the role of shear stress in changes in artery function with a novel technique that allows us to mimic exercise induced changes in large artery shear stress without having to perform contractions. In addition to responding to changes in shear stress, our arteries are controlled by nerves. Similar to the motor neurons that that stimulate our skeletal muscles to contract, the nerves that control our arteries cause the muscle in their walls to contract, making the vessel smaller (constriction). We still do not clearly understand how responses to increases in shear stress, and responses to signals from the nerves interact when they are experienced simultaneously in the same artery. To explore this we will manipulate both variables, and measure changes in artery function and structure and factors that reflect neural activity. In addition to changes in signals from nerves, when we experience something that is acutely stressful, like public speaking, this causes a hormonal response that interacts with vascular function. The proposed research will use a variety of interventions to manipulate aspects of the stress response in order to provide novel insight regarding the interaction of stress response signals and their impact on vascular function. Studies in isolated cells and animal vessels suggest that the pattern of shear stress (e.g. whether it is always in one direction or changing direction) is an important determinant of endothelial cell function. However, we know less about the impact of chronic changes in shear stress pattern in the integrated human system. This is important because several factors including different types of exercise and different levels of neurally mediated constriction can alter the pattern of shear stress in our arteries. The proposed research will use a variety of techniques to chronically expose the arteries of participant’s arms and legs to different shear stress patterns and assess the impact on artery function and structure. As a whole this research will provide important insight into the complex interaction and integration of signals in human arteries. The information gained from these studies will assist in advancing our understanding of basic human cardiovascular function. This research program will also provide a rich training environment for undergraduate and graduate students and research associates allowing them to develop skills that foster the capacity for innovation and critical thinking. This is important to support the development of research leaders and the long term success of research in Canada, which benefits all Canadians.