The mechanics of blood flow over the inner lining of arteries is a key regulator of endothelial cell function, including anticoagulation properties, vascular tone, and the barrier function. Laminar blood flow promotes these important functions, while so-called disturbed blood flow leads to a dysfunctional endothelial cell phenotype that is primed for the development of cardiovascular disease?the leading cause of death in the United States. The long-term goal of this work is to develop low intensity pulsed ultrasound into a mechanism that can noninvasively deliver a therapeutic mechanical (non-thermal) stimulus to dysfunctional endothelial cells in diseased arteries that induces the beneficial mechanobiological effects of laminar blood flow. This goal is supported by numerous studies that have shown the beneficial effects of low intensity ultrasound on cells, including endothelial cells, which operate through mechanosensitive signaling pathways. However, one limitation of these studies is the lack of consideration of the interface between mechanics and biology as the ultrasound wave interacts with the target cells. This project will address this deficiency by identifying the ultrasound regimens that activate known mechanosensitive signaling pathways within human umbilical vein endothelial cells at expression levels comparable to cells exposed to normal laminar flow. In addition, modeling will be employed to relate those ultrasound regimens to estimates of endothelial cell mechanical strains. This project will also evaluate the efficacy of low intensity pulsed ultrasound to promote the regression of atherosclerotic plaques in an established mouse model. The therapeutic efficacy of ultrasound will be compared to that of atorvastatin, a widely used pharmacologic to lower blood cholesterol levels in patients as a treatment for atherosclerosis. In addition, since this study seeks to engineer ultrasound to induce the beneficial biological effects of laminar blood flow for the purpose of developing a therapy for atherosclerosis, the therapeutic efficacy of laminar blood flow will also be evaluated as a comparator to that of ultrasound. This has not been done previously, despite the general acceptance that arterial segments experiencing laminar blood flow are protected from atherosclerosis. The central hypothesis of this project is that ultrasound can be engineered to induce the same beneficial biological effects of laminar blood flow on endothelial cells within diseased arteries, leading to normal behaviors and disease regression. This project has the potential to lead to the development of a novel ultrasonic therapy for conditions such as coronary artery disease, ischemic stroke, and peripheral artery disease that is both targeted and noninvasive. In addition, results may have significant implications for the treatment of other cardiovascular diseases, such as intracranial aneurysms. To ensure successful completion, this project leverages a multidisciplinary research team with a unique expertise in endothelial cell mechanobiology, ultrasound, atherosclerosis, and cardiovascular medicine.
Atherosclerosis is the leading cause of death and a major economic burden in the United States. There is a need for the development of new therapies that are both targeted and noninvasive. The goal of this proposal is to evaluate the efficacy of a mechanical stimulus delivered in a targeted and noninvasive manner via low intensity pulsed ultrasound as a therapeutic for atherosclerosis.