Grant: Operating Grant

Patients with Type 2 Diabetes (T2D) have a 2-4 greater risk of experiencing cardiovascular disease, such as atherosclerosis, coronary artery disease, hypertension and stroke. An early event in the development of T2D is injury to the vascular endothelium, a monolayer of cells lining the lumen of blood vessels that is critical for controlling vessel diameter and ultimately blood pressure. Injury or dysfunction of the endothelium directly contributes to the onset and severity of cardiovascular disease and it is now recognized that preventing or reversing endothelial dysfunction should improve the health of T2D patients. Using both human and rodent tissues, we have recently reported that membrane proteins (i.e. K+ selective ion channels) in vascular endothelium play a critical role in the regulation of blood vessel diameter by controlling vascular smooth muscle contraction. Moreover, manipulation of these ion channels with a novel class of drugs reverses the dysfunction of the vascular endothelium associated with T2D. In the accompanying research proposal, we will pursue these observations in order to identify the cellular defects preventing the normal activity of endothelial K+ channels and how a drug-like activator of these channels can improve vascular function in diseased blood vessels and tissues obtained from T2D rodent models and human patients. Our experiments will incorporate biochemical and functional measurements of key biological events in single endothelial cells, small arteries, intact beating hearts and whole animals that will provide critical information about T2D-associated injury to blood vessels. These proposed studies will reveal important, new insights into the cellular defects contributing to endothelial dysfunction in T2D patients and how manipulating key proteins in the vascular endothelium may lead to potential new therapeutic strategies to reverse disease-related vascular dysfunction and debilitating cardiovascular complications.