Investigating the Impact of Endothelial Dysfunction and Aging On Vascular Remodeling Using Mouse Models
Date of Award
Open Access Dissertation
Susan M. Lessner
Endothelial dysfunction, characterized by a reduction in the bioavailability of nitric oxide (NO), is a major factor in the initiation and progression of atherosclerosis, an age-related chronic inflammatory process in the arterial wall and the leading cause of mortality and morbidity globally. A better understanding of alterations in vascular structure and function associated with endothelial dysfunction can facilitate the early detection of atherosclerosis and the development of potential pharmaceutical interventions. This study aims to clarify the impact of endothelial dysfunction in conjunction with aging on the microstructure of aortic extracellular matrix (ECM) and to elucidate the relationship between microstructural adaptation and biomechanical responses during the maladaptive vascular remodeling process. Therefore, a mouse model with genetic deletion of endothelial nitric oxide synthase (global NOS3 knockout), which manifests severe endothelial dysfunction, was used to investigate the coupling effects of endothelial dysfunction and aging on hemodynamic parameters, geometrical and structural features of the arterial wall, and active and passive aortic mechanical responses. Our study revealed that endothelial dysfunction triggers substantial alterations in the microstructural organization of adventitial collagen fibers and changes in the vascular geometry with age to restore homeostatic levels of passive circumferential stress and stretch in vessels subjected to hypertension. However, endothelial dysfunction-induced changes in the microstructure and geometry of the aortic wall led to increased passive aortic stiffness. Additionally, the effect of endothelial dysfunction on the contribution of smooth muscle cell (SMC) contraction to the total mechanical response varies with time. These findings contribute to a more comprehensive depiction of aortic structural and mechanical adaptations during the maladaptive vascular remodeling process induced by endothelial dysfunction.
In addition, to further expand the repertoire of experimental techniques used in mechanical characterization of blood vessels, we explored the application of digital image correlation (DIC) in strain measurements of mouse aortas subjected to mechanical stretching. We demonstrated that a novel speckle-patterning method using colloidal gold particles is effective in creating optimal patterns to track deformation of the mouse aorta and to achieve full-field strain mapping up to the point of mechanical failure. This novel speckle patterning method shows great potential in the field of soft-tissue DIC applications.
Du, L.(2022). Investigating the Impact of Endothelial Dysfunction and Aging On Vascular Remodeling Using Mouse Models. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/7027
Available for download on Friday, December 15, 2023