Semester

Fall

Date of Graduation

2013

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Jefferson C. Frisbee

Committee Co-Chair

Gregory Dick

Committee Member

Jeffrey Fedan

Committee Member

Sarah Knox

Committee Member

Timothy Nurkiewicz

Committee Member

Shane Phillips

Abstract

Peripheral vascular disease is a pathological disease state whereby the peripheral vascular system becomes progressively limited in its ability to adequately perfuse extremities despite increases in metabolic demand. One of the primary risk factors for development of peripheral disease is the Metabolic Syndrome. It is the presentation of three simultaneous comorbidities, with obesity being the most common denominator in most metabolic syndrome patients, but also including a pro-inflammatory state, pro-oxidant state, pro-thrombotic state, increased blood pressure, atherogenic dyslipidemia, or insulin resistance. Currently, the population of the United States is approximately 75% overweight, obese, or extremely obese and the prevalence of obesity related consequences is rising, including but not limited to diabetes, cardiovascular disease, and peripheral vascular disease.;Our laboratory has demonstrated that a defining characteristic of metabolic syndrome is microvascular dysfunction. Increasing evidence has indicated that the mechanisms responsible for microvascular dysfunction in metabolic syndrome are oxidant stress-based alterations to arachidonic acid metabolism and increased sensitivity to adrenergic stimulation. However, it remains unclear if the altered microvascular reactivity that presents with metabolic syndrome plays a role in the perfusion: demand mismatch that accompanies and defines peripheral vascular disease. This dissertation seeks to understand the altered hemodynamic control found in metabolic syndrome. It set out to examine: 1. The effect of altered microvascular reactivity in metabolic syndrome on vascular tone and performance outcomes. 2. Identify the spatial and temporal alterations to perfusion distribution in metabolic syndrome. 3. Determine the effect of metabolic syndrome on erythrocyte distribution in the microvasculature and capillaries.;The results of these studies determined that a key contributor to the development, maintenance, and progression of peripheral vascular disease is microvascular dysfunction. This dysfunction increases the microvascular perfusion distribution by spatially distinct mechanisms, with adrenergic dysfunction dominating in larger microvessels and oxidant stress-based increases in thromboxane A2 dominating in smaller microvessels. Additionally, metabolic syndrome blunts the temporal compensation that would serve to attenuate the increased perfusion distribution. Combined, the spatial and temporal impairments to microvasculature serve to alter erythrocyte distribution on a network level in skeletal muscle. These data shed light on how metabolic syndrome insidiously alters microvascular control of blood flow, leading to a perfusion: demand mismatch, and ultimately contributing to pathological disease states like peripheral vascular disease.

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