Thiol regulation of vascular function and phenotype

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Blood vessels produce a number of substances that maintain the health of the cardiovascular system. The cells that make up the blood vessel wall (endothelial cells and vascular smooth muscle cells) contain antioxidant enzymes and chemical antioxidants, including glutathione (GSH), that help ensure proper functioning. Cellular GSH levels are high and this chemical is believed to make an important contribution to antioxidant capacity and vascular function. However, there is not much known about the distribution of GSH in different types of blood vessels, or about the mechanisms by which it helps promote proper vascular function. There have not been very many scientific studies that have specifically manipulated blood vessel GSH levels to study the consequences of too little or too much of this chemical, or how it interacts with other molecules in the blood vessels. The studies in this proposal aim to discover the distribution of GSH in different blood vessel types throughout the body, and to study the effects that lowering GSH levels has on the function of these vessels in controlling dilation and constriction of the vessels and the blood flow to tissues. We will also determine what the relationship is between GSH levels, vascular function, and gene and protein expression of the blood vessels. We will investigate how the blood vessels that have compromised levels of GSH respond to other stressors. In addition we will study the effects of acute and chronic exercise on blood vessel GSH levels, and will examine the effects of exercise on vascular function and characteristics in blood vessels with compromised GSH levels. These experiments will be accomplished by using a number of experimental models including intact rats, isolated blood vessels and isolated heart from rats. Understanding the role of GSH in regulation of blood vessel function is important from a basic science point of view to understand the signaling systems that are important in determining the molecular composition and the functional characteristics of blood vessels in health and in dysfunction benefiting cell and vascular biologists directly. Clinical researchers may translate it into many obvious applications that can directly impact the lives of average Canadians.