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The use of genetically modified mouse models for investigations of mechanisms of arterial stiffness

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thesis
posted on 28.03.2022, 13:49 by Kayla Dawn Viegas
Arterial stiffness is an independent risk factor for cardiovascular morbidity and mortality. With age, the large arteries become stiffer, leading to hypertension, left ventricular hypertrophy, end organ damage, and cardiovascular disease. However, the underlying cellular and molecular mechanisms leading to increased arterial stiffness remain largely unknown. The scope of the work presented in this thesis encompasses the use of genetically modified mouse models to explore potential mechanisms of vascular stiffness. A novel, high-fidelity technique of estimating aortic stiffness by pulse wave velocity (PWV) in the mouse was developed and used to characterise the pressure-dependency of PWV in the mouse aorta. Transglutaminase 2 (TG2) is a multifunctional enzyme which was hypothesized to play a role in arterial stiffness due to its ability to crosslink various structural proteins in the extracellular matrix. Pressure-dependent PWV, vascular reactivity, aortic geometry and calcification, and cardiac function were investigated in TG2-/- and wild type (WT) mice. Findings suggest that TG2 plays a role in arterial stiffness at high blood pressures and left ventricular hypertrophy. The apolipoprotein E knockout (apoE-/-) mouse is a widely used model of human atherosclerosis. In vivo PWV measurements demonstrated increased stiffness in apoE-/- mice compared to control as early as 12 weeks of age. Endothelial dysfunction through an impaired relaxation response to acetylcholine was also observed. A study of the effects of early aging on vascular stiffness in the mouse was also performed. Between the ages of 12 and 36 weeks a significant increase in aortic stiffness was observed in WT mice. A slight but insignificant increase in PWV was observed in the apoE-/- mouse suggesting that the rate of change of PWV is strain dependent. The nitric oxide synthase inhibitor, L-NAME, was used to induce both increased TG2 activity and endothelial dysfunction, with the hypothesis that this would increase arterial stiffness. In TG2-/- mice and WT control, no differences in cardiovascular function were observed after L-NAME treatment. However, in 12 week old apoE-/- mice, L-NAME administration reduced PWV, suggesting the presence of compensatory mechanisms that account for the lack of nitric oxide bioavailability. This thesis provides new insights into potential mechanisms of increased vascular stiffness. More importantly, it highlights the utility of the genetically modified mouse as a tool for interrogating novel pathways to arterial stiffness, and a new method with which to do so. Use of this technique could lead to the identification of novel therapeutic targets for the treatment of vascular stiffness.

History

Table of Contents

Chapter 1. Introduction -- Chapter 2. Literature review -- Chapter 3. Aortic pulse wave velocity measurement in the mouse : method development -- Chapter 4. Characterisation of pressure dependency of aortic PWV in the mouse -- Chapter 5. Effect of transglutaminase 2 on arterial stiffness -- Chapter 6. Transglutaminase 2 and arterial stiffness : effect of increased duration of NOS inhibition -- Chapter 7. Arterial stiffness in apolipoprotein E knockout mice -- Chapter 8. Effect of age on pressure-dependent PWV in the mouse -- Chapter 9. Conclusion.

Notes

Bibliography: pages 221-237 Theoretical thesis.

Awarding Institution

Macquarie University

Degree Type

Thesis PhD

Degree

PhD, Macquarie University, Faculty of Medicine and Health Sciences, Australian School of Advanced Medicine

Department, Centre or School

Australian School of Advanced Medicine

Year of Award

2014

Principal Supervisor

Alberto Avolio

Additional Supervisor 1

Mark Butlin

Rights

Copyright Kayla Dawn Viegas 2014. Copyright disclaimer: http://www.copyright.mq.edu.au

Language

English

Extent

1 online resource (xxx, 238 pages) colour illustrations

Former Identifiers

mq:44126 http://hdl.handle.net/1959.14/1066509