Project 462195

Peripheral arterial disease and diabetic foot ulcer are a major risk factor for lower-extremity amputation and a major cause of morbidity and premature death in patients with diabetes. Evidence suggests that elevated glucose levels are the most important causal factors of impaired new blood vessel formation, an essential process to prevent critical limb amputation. We recently discovered that the activation of a system called Apelin might create new blood vessels in diabetic rodents. In addition, our research team has uncovered several proteins in patients with diabetes and peripheral arterial disease that make then prone to amputation. However, animal and clinical studies are required to validate if these factors can be used as biomarkers to predict patients with diabetes at risk of amputation. Our research team proposes to evaluate the impact of a treatment with the Apelin system and investigate new clinical therapeutic targets to improve blood flow of the ischemic limb. To accomplish this aim, we will use genetically modified mice of Apelin receptor (responsible to initial signals of the Apelin system) in two cell types that compose blood vessels. We will investigate the role of the Apelin system in specific vascular cells as well as measure blood flow and muscle function in nondiabetic and diabetic mice. Furthermore, we intent to recruit patients with and without diabetes that require major limb amputation (patient with peripheral arterial disease) or reconstruction (patients without peripheral arterial disease). Vessels and muscle biopsies will be collected from the amputated and reconstructed limb. Validation of our proteins of interest will be measured on the collected tissues of patients with diabetes, without diabetes and without arterial diseases. Our research project will offer innovative mechanistic tools to develop new strategies to promote new blood vessels during ischemia and prevent extremity amputation in patients with diabetes.