Project Summary/Abstract A thoracic aortic aneurysm is a disease process that involves dilation of the vessel caused by a weakening of its wall. This dilation of the aorta has the potential to lead to rupture and death unless treated with a dramatic surgical intervention to replace the diseased aorta. Indications for surgery largely rely on size and often fail to capture all of those at risk for rupture and death. While various theories have been put forward, the molecular and biomechanical causes of aortic wall weakening have not been elucidated. Consequently, novel therapies to prevent or reverse this disease process have not been produced. The aortic wall consists of three layers identified as the intima, media, and adventitia. In aortic aneurysm, smooth muscle cell death and elastin fiber fragmentation is typically observed in a process termed cystic medial degeneration. While many studies have previously focused on the aortic media, recent work has placed focus on the outer layer of the aorta. The aortic adventitia contains numerous small blood vessels known as vasa vasorum which provide blood flow to the outer half of the aortic wall. The vasa vasorum are made up of endothelial cells and supportive pericytes which regulate flow through these vessels. A recent study in our lab has revealed deficient and dysfunctional vasa vasorum in aneurysmal human aorta. Hypoxia in the outer half of the aorta and a decrease in growth factors associated with blood vessel formation were also observed. Based on this knowledge, we posit that a reduction in perfusion from vasa vasorum dysfunction leads to hypoxia and subsequent aortic wall weakening. This study aims to examine this disease process at the level of the pericytes which support the vasa vasorum. Preliminary findings have revealed that human aortic aneurysm-derived pericytes involved in the formation and maturation of vasa vasorum are dysfunctional. In addition, extracellular matrix (ECM) from human aneurysmal aortic tissue produces deleterious effects on normal aortic pericytes and endothelial cells. Given these findings, we hypothesize that aortic aneurysm arises from dysfunction in the cells and extracellular matrix that contribute to vasa vasorum formation. Specific Aim 1: Compare function of vasa vasorum pericytes and human adventitial ECM from aneurysmal and normal aortic tissue Specific Aim 2: Investigate therapeutic applications of porcine ECM in rabbit aneurysm model Through this study, we seek to identify targets for novel therapeutic biomaterials such as porcine extracellular matrix hydrogel. Our long-term goal of this project is to improve identification of those at risk for aortic dissection or rupture and to provide less-invasive treatment modalities that prevent the sequelae of thoracic aortic disease.