Integrated Microvascular Flow Regulation and the Impact of Metabolic Disease
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.
Microcirculation, rodent models of metabolic disease, obesity and insulin resistance, machine learning, regulation of vascular tone, cerebral vasculopathy
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