Grant: Operating Grant

Vascular endothelium is a cell layer that lines the lumen of blood vessels and regulates blood pressure by producing and releasing chemical substances that regulate the level of contraction in the smooth muscle layers in the wall of the blood vessel. In diabetes mellitus, dysfunction of the endothelium is considered clinically to be an early causative event that leads to more serious cardiovascular complications, such as atherosclerosis, kidney damage and heart failure. Preventing or reversing endothelial dysfunction should thus halt the progression of cardiovascular disease. In the accompanying research proposal, we will examine the cellular mechanisms underlying the synthesis and actions of nitric oxide (NO), an important vasoactive substance produced by the endothelium that lowers blood pressure by relaxing smooth muscle and further acts to prevent the formation of atherosclerotic plaques. In particular, we will define the critical roles for membrane ion channels and cell signaling pathways in the synthesis of NO by human endothelial cells and in active resistance arterioles from mouse models of human diabetes. Our experiments will incorporate biochemistry, molecular biology and state-of the-art recording techniques to measure directly NO production and ion channel activities in single endothelial cells. These proposed studies will reveal important, new insights regarding NO synthesis and action in blood vessels, as well as potential new therapeutic strategies to reverse disease-related changes in these events.