Grant: Project Grant

Patients with Type 2 Diabetes (T2D) have a 2-4 greater risk of acquiring cardiovascular (CV) disease, such as hypertension, coronary artery disease, atherosclerosis and stroke. An early event in the progression of T2D-associated CV disease is injury to the vascular endothelium, a layer of cells lining blood vessels that is critical for controlling blood pressure and blood flow to tissues. Endothelial dysfunction directly contributes to the development of CV disease and cardiologists have long sought treatments to reverse endothelial dysfunction as a strategy to improve health in T2D patients, with limited success. Our research over the past 10 years has revealed that endothelial function can be restored in arteries from T2D humans and rodents by targeting specific proteins (i.e. K+ selective ion channels) in the endothelium that are critical for regulating blood pressure. More recently, we have observed that this same strategy can improve long-term CV health in rodents with T2D. We will pursue these fundamental results in our proposed research by identifying the cellular mechanisms through which endothelial K+ channel activity maintains vascular health and further examine how this activity restores normal function in diseased arteries from T2D patients and rodents. Experimentally, we will identify the key cellular pathways in arteries that are regulated by endothelial K+ channel activity, and then demonstrate that the selective targeting of these same K+ channels can improve blood pressure regulation and tissue blood flow in a pre-clinical rodent model of human T2D. These proposed studies will thus reveal important, new knowledge into the cellular deficits contributing to endothelial dysfunction in T2D patients and how they can be overcome by targeting K+ channel proteins in the blood vessel wall. These discoveries may thus lead to a new therapeutic approach to reverse T2D-associated vascular injury and CV disease.