Date of Award
Summer 9-11-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Thoracic aortic aneurysms (TAA), characterized by dilation of the aortic wall, are a major health concern that can cause aortic dissection, rupture, and death. The underlying pathology of TAA is not fully understood but is associated with fragmentation of elastic fibers in the wall extracellular matrix. Genetic mouse models allow us to investigate how mutations in elastic fiber associated proteins that have been identified in human TAA affect elastic fiber structure and how structural changes in the elastic fibers may contribute to TAA progression. Using these mouse models, we investigate the hypothesis that elastic fiber fragmentation will facilitate transmural mass transport and contribute to TAA pathology. Additionally, we propose that pentagalloyl glucose (PGG), a strong gallotannin, may prevent and/or restore mechanical function in chemical and genetic mouse TAA models through stabilization of the elastic fibers. In this work, mass transport parameters were determined for two different genetic mouse TAA models with elastic fiber fragmentation. It was found that elastic fiber fragmentation impacts solute permeability of the aortic wall and that an increase in diameter correlated with fluid flux, solute flux, and metrics of elastic fiber fragmentation. These data show that changes in mass transport may contribute to TAA pathology and provide aortic wall transport properties for further computational models or pharmacokinetic analyses for drug delivery. Also, PGG was able to both prevent and restore mechanical changes in the aorta in an in vitro chemical mouse model of TAA. In vivo delivery of PGG in a genetic mouse TAA model showed limited success and requires further research to optimize delivery conditions of the PGG carrier nanoparticles. Overall, this work demonstrates connections between elastic fiber fragmentation and TAA that may be leveraged for TAA treatment. Often described as a ‘silent killer’, and a better understanding of TAA pathology and a preventative drug treatment could be lifesaving.
Language
English (en)
Chair
Jessica Wagenseil