Date of Graduation


Document Type


Degree Type



School of Medicine


Physiology, Pharmacology & Neuroscience

Committee Chair

Jefferson Frisbee.


The metabolic syndrome is a multi-faceted disease state in which the initial pathology of obesity leads to the development of a cadre of comorbidities including, but not limited to, atherogenic dyslipidemia, a prothrombotic state, a proinflammatory state, a pro-oxidant state, hypertension and type II diabetes mellitus. The prevalence of obesity is drastically increasing both nationally and globally, indicating that understanding obesity related disease is more relevant now then ever before. The metabolic syndrome has been demonstrated to result in numerous deleterious consequences for afflicted individuals, not the least of which is peripheral vascular disease. While the study of peripheral vascular disease has been extensively conducted and a robust body of literature exists implicating alterations in vasomotor regulation as the etiology for demand:perfusion mismatches in peripheral tissues, little study has been conducted to determine the consequences of metabolic syndrome on vascular network structure and the perfusion outcomes of the alterations to that network.;Our lab has previously demonstrated that with metabolic syndrome comes a progressive loss of microvessel density in skeletal muscle, termed rarefaction. This rarefactive phenomenon has been established in other animal models as well as in humans, however, the mechanistic underpinnings of microvascular rarefaction still require significant investigation. For this reason we set out to:;1. Identify the significant physiologic correlates/predictors of microvascular rarefaction. 2. Determine which correlates played a contributing role in the development of rarefaction. 3. Better establish a time-course for the phenomenon of rarefaction in our experimental model; the obese Zucker rat.;The results of these studies demonstrate that alterations to inflammatory status and elevated oxidant stress significantly contribute to the development of obesity related rarefaction. Additionally, these two causative-agents act through intermediaries either shifting the balance in endogenous prostanoid production to a preferential generation of TxA2, or diminishing vascular nitric oxide bioavailability. Additionally, it was discovered that in the obese Zucker rat, rarefaction is a biphasic process wherein the phases are mechanistically distinct from one another. The initial or early phase of rarefaction is mediated by elevations in TxA2 production, whereas later rarefaction is mediated by diminished vascular nitric oxide bioavailability. Taken together, these data indicate that rarefaction is a process whose origins are rooted in the very earliest development of metabolic syndrome. The process itself is more mechanistically complex than initially anticipated and is mediated by pathologic alterations (elevated oxidant stress and altered inflammatory profile) which have been shown to produce additional deleterious effects. These studies would indicate that a greater knowledge of the origins and regulation of alterations to inflammatory status and elevations in oxidative stress are essential in treating metabolic syndrome.