Grant: Operating Grant

The hardening of arteries (atherosclerosis) is one of the main ways that cardiovascular disease can lead to death. Atherosclerosis starts when the cells lining the inside of blood vessels (endothelial cells) become damaged and the blood vessel loses the ability to expand. Nearly all treatments for atherosclerosis aim at treating the disease in the later stages. There is a growing need to treat the disease in the early stages, to ensure arteries remain flexible and resistant to cardiovascular disease. Autophagy is a process that is activated under stressful conditions and involves degradation and subsequent recycling of cellular components. Current evidence suggest that autophagy may be crucial in preventing or impeding the progression of certain chronic diseases. Our objective is to determine if ATG7, a gene that is critical to normal autophagic responses, can help protect endothelial cells and preserve the ability of blood vessels to expand and/or sprout. We have made a mouse that does not have the ATG7 gene in endothelial cells. We will divide these mice (and normal mice) into several groups and compare blood vessel function and recovery under normal conditions and following ischemia (short-term loss of blood flow). We will also breed the mice that do not have the ATG7 gene in their endothelial cells with another strain of mice that spontaneously gets atherosclerosis to see if the disease is worse in the absence of ATG7. Finally, we will compare the blood levels of proteins known to participate in autophagy with endothelial function and the extent of atherosclerosis in humans. We believe that our proposed research approaches will yield novel insights into the role of endothelial cell autophagy in the initiation and advancement of vascular disease and uncover an innovative treatment approach for atherosclerosis and its complications.