Notch Enhances Shear-Mediated Arteriogenesis in Cerebrum
Initial Award Abstract
Occlusive arterial disease, including stroke and heart attack, is the leading cause of mortality and morbidity in Americans. Cigarette smoke dramatically increases the possibility of arterial occlusion, putting smokers and those affected by secondhand smoke at further risk. There is significant interest in developing molecular therapy to stimulate blood vessel growth and improve blood flow to dying tissue. In humans, arterial occlusion results in “arteriogenesis”, a process by which small arteries grow into larger conduit arteries that reroute blood and improve flow. The capacity of pre-existing arteries and their growth following occlusion is strongly affected by genetic background, resulting in a wide range of outcomes. Increased blood flow in these collateral vessels promotes “arteriogenesis” but the biochemical signaling mediating this growth is not well understood. We have developed a mouse model of “arteriogenesis”. In this model, we are able to either turn off or increase the production of a protein that regulates arterial identity in blood vessels throughout the body. Lack of this protein inhibits a normal level of artery growth after arterial occlusion. The goal of our study is to determine how this protein is important for “arteriogenesis”, and how it is regulated in blood vessels after arterial occlusion. We use advanced imaging in live mice to study how arteries grow, with the ability to observe cell behavior and blood flow with exquisite detail.
The success of this work will greatly advance our understanding of the biological mechanism controlling “arteriogenesis”, thus helping in the development of treatments for diseases associated with arterial occlusion. Our research will also lead to technological advances for studying vascular development in vivo. We expect this work to help the development of treatments for patients suffering from arterial occlusion. Since smokers have an elevated risk of arterial occlusion, we expect that this research will benefit smokers and those affected by secondhand smoke. |