Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Biochemistry

Supervisor

Dr. Geoffrey Pickering

Abstract

The thoracic aortic wall can degenerate over time with catastrophic consequences. Vascular smooth muscle cells (SMCs) can resist and repair artery damage but their capacities decline with age and stress. Recently, production of NAD+ via nicotinamide phosphoribosyltransferase (Nampt) has emerged as a mediator of cell vitality. However, a role for Nampt in aortic SMCs in vivo is unknown. To study the role of Nampt in SMCs, mice with Nampt-deficient SMCs were generated. SMC-Nampt knockout mice were viable but had mildly dilated aortas. Infusion of angiotensin II led to aortic medial hemorrhage and dissection. SMCs had indicators of premature senescence and there was evidence for oxidized DNA lesions and breaks. Evaluating ascending aortas from patients with dilated aortopathy revealed an inverse relationship between SMC-NAMPT content and aortic diameter. Unrepaired DNA strand breaks in low NAMPT SMCs were indentified. NAMPT promoter analysis revealed CpG-hypermethylation within the dilated aorta, which inversely correlated with NAMPT expression. Global transcriptome analysis of Nampt-knockout SMCs revealed a shift in the transcription of genes associated with the ECM. This was associated with corresponding changes in extracellular matrix content in SMC-Nampt knockout mouse aortas. Finally, by generating a global Nampt-knockout mouse, I determined that Nampt ablation in the adult was quickly lethal. These findings reveal new processes for SMC health and functionality, with important implications for mitigating the consequences of the accumulation of the stresses that push blood vessels to failure.

Available for download on Saturday, November 30, 2019

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