Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Medical Biophysics
Supervisor
Frisbee, Jefferson C
Abstract
The growing prevalence of metabolic diseases poses a significant challenge to public health. One of the steadily emerging challenges facing individuals suffering from chronic metabolic disease is the development of cardiovascular diseases. While cardiovascular diseases may affect any part of the body, it is at the level of the arterioles where the most dynamic changes occur. These impairments may lead to a variety of functional deficits which are particularly detrimental when they result in cognitive impairments, including increasing depressive symptom severity. Prior to any detailed investigation into the mechanistic underpinnings contributing to the altered behaviour of arteriolar networks in tissue with chronic metabolic disease, it is imperative that we begin to understand the fundamental relationships of arteriolar behaviour under normal healthy conditions.
The reactivity of ex vivo proximal and in situ distal resistance arterioles from rat skeletal muscle was systematically determined when challenged by one-, two-and three-parameter combinations of five major physiological stimuli (norepinephrine, intravascular pressure, oxygen, adenosine (metabolism) and intralumenal flow). Predictive machine learning models determined which factors were most influential in controlling the diameter and rate of arteriolar responses. Sympathetic and metabolic influences were shown to be the most robust and stable in the proximal and distal arterioles respectively.
With these relationships established, the impact of metabolic disease on these integrated vascular behaviours was investigated in a model of metabolic disease, the obese Zucker rat. Increased myogenic activation was shown to have unexpected protection to endothelial production of dilator metabolites in the presence of impaired endothelial-dependent dilation. This illustrates the complexity of interaction between mechanisms of arteriolar tone regulation. Finally, using a multi-scale approach incorporating plasma biomarkers, vascular structure and function, tissue oxygenation through biosimulation, and behavioral outcomes related to depression, the relationship between metabolic disease, cerebrovascular function, and depressive symptoms was examined. Depressive symptom severity correlated with the extent of cerebrovascular rarefaction and interventions targeting thromboxane production blunted rarefaction and depressive symptoms. These studies not only contribute to the fundamental understanding of arteriolar behaviour but also to relevance of said impairments in the development of poor functional outcomes brought on by increasing metabolic disease severity.
Summary for Lay Audience
Metabolic diseases greatly increase the risk of developing cardiovascular diseases. While cardiovascular diseases may affect any part of the body, some of the most dynamic changes occur in the small blood vessels called arterioles. These impairments may lead to a variety of functional deficits related to blood flow regulation which are particularly detrimental if they occur in the arterioles of the brain and result in cognitive impairments such as depression. Before looking at the mechanisms of these changes in disease there is a need to increase our understanding of how these small blood vessels take in the various physiological signals they are exposed to in the body and use them to regulate blood flow. The responses of two sizes of arterioles from rat skeletal muscle were systematically determined in response to physiologically relevant stimuli and analyzed using machine learning models. Results found that influences related to the fight or flight, sympathetic system were most significant to the larger proximal arterioles and metabolic influences impacted the smaller distal blood vessels the most.
Following these more foundational studies, the changes to blood flow regulation at the level of these small blood vessels was determined in metabolic disease using the obese Zucker rat. It was found that an increase in the regulatory mechanisms that respond to changes in pressure inside the blood vessels are associated with a decreased ability to promote blood flow, even when the production of dilating substances is preserved. Finally, the relationship between metabolic disease, brain vascular function, and depressive symptoms was explored using blood biomarkers, vascular structure and function, simulation of tissue oxygen levels, and behavioral outcomes related to depression. Depressive symptom severity was associated with the loss of small brain blood vessels and treatments targeting a specific thromboxane pathway blunted these impairments. These studies both contribute to the fundamental understanding of the behaviour of blood vessels and underscore the intricate relationship between metabolic disease, vascular function, and brain health.
Recommended Citation
Halvorson, Brayden D., "Integrated Microvascular Flow Regulation and the Impact of Metabolic Disease" (2024). Electronic Thesis and Dissertation Repository. 10115.
https://ir.lib.uwo.ca/etd/10115