Date of Award

Spring 2021

Document Type

Open Access Dissertation

Department

Biomedical Engineering

First Advisor

Susan M. Lessner

Abstract

Aneurysm of the ascending aorta is the most common type of thoracic aortic aneurysm, and it is a life-threatening manifestation of Marfan syndrome (MFS), a connective tissue disorder caused by mutation of the FBN1 gene. Incidence of Marfan syndrome is similar for men and women; however, men suffer from more severe aortic events compared to women.

This study aims to provide a better understanding of age and sex dependency of cell and extracellular matrix alterations of the aortic wall during the progression of the aneurysm caused by Marfan syndrome. To achieve this goal, the C1041G/+ mouse model of Marfan syndrome was used. By including 3 to 12 months old male and female mice in the study, age and sex dependency of the disease progression and involvement of progenitor cells were studied.

Aortic dilation occurs in both male and female MFS mice; however, pattern and extent of the dilation differ between them. Female mice have a slow and insignificant increase in aortic diameter with age, while male mice show a sudden increase of diameter between 6 and 9 months of age that indicates the age dependency of aneurysm progression in male mice. Aortic dilation in female MFS mice never reaches the levels of male mice, which emphasizes that male mice suffer from more severe aortic pathology compared to females. Aortic dilation is a consequence of changes inside the aortic wall. Elastin breaks, which are one consequence of deficient fibrillin-1 production, trigger a series of cellular and molecular changes. While number of elastin breaks is similar in male and female MFS mice up until very late ages, other events are highly sex dependent. Staining for specific markers of contractile smooth muscle cells shows that contractile cells diminish from the aortic media of male and female MFS mice. However, even in the healthy aorta, old male mice show fewer contractile cells compared to old females, which emphasizes the effect of aging on male mice. Loss of contractile SMCs correlates with the findings from myography that show decreased contractility of the aortic wall for Marfan mice compared to healthy mice.

Furthermore, changes in the aortic extracellular matrix were assessed and compared between male and female mice. Similar to the rest of the findings of this study, female MFS mice and WT mice show similar levels of medial collagen at all ages. However, male MFS mice have significantly higher collagen deposition at 9 and 12 months compared to healthy mice, with significantly higher levels at old ages compared to young ages. The high levels of deposited collagen in aortic media at late ages correlate with higher stiffness of aortic walls measured with myography.

This study further showed that during progression of the aneurysm, the population of adventitial Sca-1+ progenitor cells increases at early ages for both male and female MFS mice. Using lineage tracing, it was shown that these cells contribute to the population of medial cells and that their contribution is similar between male and females.

Rights

© 2021, Nazli Gharraee

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