Year 4

Coronary heart disease, the major cause of morbidity and mortality in our society, results from blockage of the coronary arteries that supply blood to the heart muscle. Blockage of the coronary arteries causes heart attack. Angioplasty and stenting are used to open the obstructed coronary artery and maintain the arterial patency. ~1.3 million angioplasty and stenting procedures are performed in the US every year to treat coronary artery disease. However, these procedures activate a population of vascular cells to grow into the arterial lumen, causing re-narrowing of the artery. This re-narrowing (restenosis) is the major hurdle limiting the success of angioplasty and stenting. Mental stents coated with drug inhibitors of cell growth (drug eluting stents, or DES) reduce re-narrowing; however, considerable concerns have emerged regarding the safety of DES due to an increased risk of sudden stent occlusion by platelet aggregates (or thrombosis) and the need for prolonged anti-platelet therapy, which poses bleeding risks. Defining the mechanisms that control re-narrowing of injured arteries is therefore important for treating coronary artery disease.

The arterial wall contains a population of stem cells. These stem cells are activated when arteries are injured by mechanical stress such as angioplasty and stenting. Activation of these cells directly contributes to arterial re-narrowing. Our goal is to understand how these stem cells are activated by vessel injury, how injury signals these cells to divide and invade the vessel lumen, what molecular effectors control the cellular responses, and how to intercept these signals and effectors to prevent vessel re-narrowing. We developed new methods for isolating and growing these vascular stem cells in test tubes, and we have successfully used these methods to determine how arterial injury or mechanical stress signals the stem cells to produce different types of cells which grow into the arterial lumen, causing narrowing of the artery. In the past year, we developed new genetic tools to further understand the mechanism of vascular injury and repair. We are using the new genetic tool to define molecular and cellular pathways that control the reaction of stem cells to arterial injury.