Date of Award

2016

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Susan Lessner

Abstract

The aortic extracellular matrix (ECM) consists of microstructural proteins, collagen and elastin, together with proteoglycans and other components. The matrix metalloproteinases (MMPs) are proteolytic enzymes that influence morphological and structural changes in the ECM and can degrade the matrix as it responds to cellular behaviors such as angiogenesis, apoptosis, proliferation, and migration. Collagen is the most important component among the extracellular proteins because it provides strength and stability to the tissue. Changes in collagen content play a major role in the development of atherosclerosis. These changes can be induced by increased or decreased proteinase activity. Therefore, we studied the collagen fiber angle distribution in mouse models of atherosclerosis with or without a deficiency of a selected MMP. Quantification of the collagen fiber data is meaningful in providing insight into the mechanical behavior of the artery and leads to an understanding of how the diseased aorta maintains homeostasis. Furthermore, such data can be utilized to increase the understanding of disease progression, including but not limited to atherosclerosis and aortic aneurysm development.

We characterized collagen fiber angles in mouse models of atherosclerosis which were fed a control chow diet or a high-fat Western diet for 6 months. To visualize collagen, we imaged the mouse thoracic and abdominal aorta using second-harmonic generation (SHG) microscopy. Angle measurements were acquired using a well-established computer software program, Continuity 6.4b. The angle measurements were exported into bivariate histograms. We then designed a multiple regression analysis to compare the distributions of absolute angles between two diet groups, controlling for diet, mouse strain, anatomical location, and radial position in the aortic wall. Data extracted from bivariate histograms were analyzed in R, a programming language and statistical software.

In trying to understand the changes seen between chow diet and Western diet fed mice, we began to study physiological variables such as blood pressure and blood flow velocity. While we did not find any differences in the hemodynamics, we were able to determine that factors beyond atherogenesis, for example aging, influenced aortic collagen fiber angle distributions. With aging and atherosclerosis, the extracellular matrix may experience an increase in collagen content and fibrous tissue. We evaluated changes in fractional collagen amount, in particular, collagen type I. To understand if changes in collagen fibers are initiated by endothelial dysfunction (a pathological condition that often accompanies atherosclerosis progression), we performed immunohistochemical studies of two endothelial cell-derived factors, intercellular adhesion molecule-1 (ICAM-1) and endothelial nitric oxide synthase (eNOS).

This study yielded data of collagen fiber angle distributions throughout the vessel wall in the aortas of mice with atheroprone phenotypes at different ages and on different diets. Endothelial dysfunction as a stimulus for vascular remodeling remains inconclusive. However, we conclude that the aorta displays a distinct remodeling response in the presence of atherogenic stimuli, even in non-lesioned areas, as observed by a shift in collagen fiber orientation.

Rights

© 2016, Shana Roach Watson

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