Endothelial Mechanotransduction in Thoracic Aneurysm Formation and Progression

点击翻译按钮获取中文摘要

Project Summary This project is based on the view that aneurysms represent a pathological response to high wall strain in which the artery wall thins and weakens instead of thickening and strengthening as it does in normal compensatory artery wall remodeling. We hypothesize that inflammatory effects of endothelial cell responses to disturbances in blood flow, and from altered signaling due to extracellular matrix remodeling are important drivers of this switch from compensatory to pathological remodeling. The proposed experiments will test these hypotheses and elucidate mechanisms that link inflammation to aneurysm initiation or progression. We will use two complementary model systems. The first is Marfan syndrome (MFS) mice, which develop severe pathological vascular remodeling and thoracic aortic aneurysms due to a defect in fibrillin 1. The second is continuous infusion of two vasoconstrictors, which induce either compensatory vascular remodeling or moderate pathological remodeling in response to elevated blood pressure. Comparison of these systems will therefore allow us to identify differences between physiological and pathological remodeling of the aorta. Aim 1 will test the effects of mutations in a critical flow-sensing gene that specifically abolish mechanotransduction pathways without compromising overall functions (with Cores B and C). In Aim 2, we will test effects of mutations in integrins and interacting molecules that specifically affect the inflammatory aspects of matrix remodeling (with Cores B and C). In Aim 3, we will investigate the role of flow in regulating expression of Angiotensin II receptor 1, a well- established mediator of aneurysm formation (with Project 1 and Cores B and C). We will also contribute expertise in mechanotransduction to studies in Projects 1, 2 and 4. Results from these experiments will provide an understanding of how specific inflammatory pathways contribute to thoracic aortic aneurysms (TAAs) and thereby identify potential new targets for pharmacological intervention.