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Notch promotes arteriogenesis in smoke-related limb ischemia

Institution: University of California, San Francisco
Investigator(s): Rong Wang, Ph.D.
Award Cycle: 2009 (Cycle 18) Grant #: 18XT-0145 Award: $250,000
Subject Area: Cardiovascular Disease
Award Type: Exploratory/Developmental Award

Initial Award Abstract
Peripheral arterial disease (PAD) occurs when the arteries that supply blood to the arms and legs are narrowed by plaque build-up the arteries, decreasing blood flow throughout the entire body. Cigarette smoking increases a person's risk of developing PAD by more than 10-fold and is considered one of the most significant risk factors in this disease. Poor blood flow caused by PAD often results in pain at rest, non-healing wounds, and infection. PAD affects 8-10 million patients in the United States alone and leads to approximately 150,000 major limb amputations each year. To restore blood flow to the areas of the body affected by PAD, small terminal ends of arteries called arterioles must expand. The molecular mechanism by which these vessels expand is unknown, and we hypothesize that Notch1, a protein that sits on the surface of the cells of blood vessel walls, is crucial in this process. Recent evidence suggests that Notch1 is required for blood flow recovery in mice whose arteries have been experimentally blocked. A modified form of Notch1 that is always "on", or active, leads to vessel expansion, making it an ideal candidate with which to treat patients with PAD. The goal of this project is to test our hypothesis that the Notch1 protein is a regulator of artery growth and can promote restoration in blood flow after arterial blockage in rodents. We will also test if the always-active Notch can enhance blood flow recovery in mice exposed to cigarette smoke. The first step of this project is to determine if the levels of the Notch1 protein in mice are increased when the mice experience reduced blood flow under experimental vessel blockage, and if these protein levels are affected by cigarette smoke exposure (Aim 1). If Notch1 is required to help expand blood vessels, it follows that there may be more of this protein present at a time when blood vessels need to be expanded. We will next confirm that Notch1 is required for blood vessel growth after blockage by comparing blood flow recovery in mice with and without the Notch1 gene whose vessels are blocked experimentally (Aim 2). We can measure the blood flow rate of these mice and determine if the presence of Notch1 makes a difference in their blood flow recovery. We expect that mice without the Notch1 gene will have less blood flow recovery after vessel blockage than mice with the Notch1 gene. Next, we will test if always-active Notch1 enhances blood flow recovery after experimental blood vessel blockage. We will determine if smoking affects blood flow recovery after experimental vessel blockage, and if the negative effects of smoking on blood flow recover can be overcome using an always-active Notch1 (Aim 3). Demonstration that Notch1 can affect a mouse’s ability to recover from reduced blood flow may lead to new therapeutics involving induction of blood vessel expansion through molecular targeting. Results from this work may have significant therapeutic implications for many tobacco-related diseases including PAD, ischemia (reduced blood flow), heart attack, and stroke.