The influence of shear stress and sex hormones on vascular function and structure

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Arteries are composed of a ring of connective tissue and muscle lined by a single layer of cells called the vascular endothelium. Constantly exposed to the frictional force of the flowing blood (shear stress) endothelial cells play a major role in determining arterial function and structure. The endothelium has the capacity to release substances that relax the muscle in the arterial wall, which widens (dilates) the artery and allows more flow. Endothelial cell function can be determined by applying specific stimuli (e.g. drugs or increasing shear stress) and then measuring the arterial dilation. A larger dilatory response is indicative of better endothelial function. The stiffness of arteries refers to the degree to which they can be distended by pressure. This capacity is influenced over the long term by structural changes in the composition of the vascular wall. In the short term, changes in blood pressure and in the contraction (tone) of the muscle in the arterial wall result in acute changes in arterial stiffness. In my research program we assess endothelial function in large and small vessels in the upper and lower limbs and assess arterial stiffness in the central arteries (near the heart) and peripheral arteries (in the limbs). This will gives us a whole body, multifaceted understanding of vascular function and structure in healthy men and women. In the proposed research we will use innovative techniques to address key gaps in understanding regarding how arteries are influenced by sex differences and experiences encountered in daily life. The proposal includes four specific short term objectives: 1) To characterize the impact of cyclic fluctuation in the primary female sex hormone estrogen over multiple menstrual/oral contraceptive pill cycles; establishing whether there are consistent `trait-like' individual differences. 2) To identify and explain the interaction between estrogen level and vascular responses to acute challenges (e.g. an acute, stressful event). 3) To characterize regional differences in the impact exercise training characteristics (duration and intensity). 4) To establish the impact of artery size on the ability of endothelial cells to respond to increases shear stress; this is critical to comparing responses in men and women. The proposed research will advance our understanding of vascular physiology in the integrated human system. Study design and execution will be lead by undergraduate and graduate students, supporting a rich training environment which develops 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.