Graduation Date

Fall 12-16-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Molecular Genetics & Cell Biology

First Advisor

Bernard T. Baxter

Second Advisor

Wanfen Xiong

Abstract

Aortic aneurysm is a widespread condition, characterized by dilation and weakening of the aortic vessel wall. Dissection and rupture of the aorta due to uncontrolled aneurysm progression carries a high risk of death. Although both thoracic aortic aneurysms (TAA) and abdominal aortic aneurysms (AAA) share similar risks of rupture and mortality, the pathophysiology of each disease is unique. TAA is a hallmark feature of Marfan syndrome (MFS), a connective tissue disorder characterized by malformation of functional elastic fibers in the aortic extracellular matrix (ECM). This malformation of elastic fibers is attributed to mutation of the gene encoding the fibrillin-1 protein, FBN1. Poorly developed elastic fibers in MFS results in numerous structural issues and dilation the ascending aorta, most often localized to the aortic root. Premature differentiation of aortic smooth muscle cells (SMC) towards a contractile phenotype is characteristic of TAA and has been shown to exacerbate its development. The results presented in this dissertation indicate that inhibition of Notch3 helps preserve the aortic extracellular matrix (ECM), improve survival, and reduce aortic dilation in TAA by limiting premature differentiation of SMC to a contractile phenotype. AAA is a dilation of the descending abdominal aorta characterized by chronic inflammation, degradation of ECM elastin, and SMC phenotypic switching and apoptosis. Elastic lamellar organization and ECM structure are preserved in the aortic wall of hyperglycemic AAA mice compared to euglycemic AAA mice. Lysyl oxidase (LOX) enzymatic activity is upregulated in AAA tissue from hyperglycemic mice, indicating that increased crosslinking of elastin may play a protective role in the hyperglycemic inhibition of AAA. Inappropriate SMC phenotypic switching and degradation of elastic fibers in the aortic ECM are factors present in both TAA and AAA. Thus, these findings have potential implications for the treatment of aortic aneurysms across a variety of etiological patterns.

Comments

2022 Copyright, the authors

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