Date of Award

Spring 1-1-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Christopher A. DeSouza

Second Advisor

Monika R. Fleshner

Third Advisor

Kenneth P. Wright

Fourth Advisor

Robert S. Mazzeo

Fifth Advisor

Brian L. Stauffer

Abstract

Microparticles are small (0.1-1.0 μm in diameter) extracellular vesicles derived from the plasma membrane of activated and/or apoptotic cells. Once thought to be inert cellular debris, microparticles are now recognized as important paracrine/endocrine vectors involved in the transcellular exchange of physiological and pathological information. Moreover, microparticles play key roles in the development of atherosclerotic cardiovascular disease and may serve as sensitive biomarkers of disease risk, progression, severity and outcome. Critical to the utility of microparticles as biomarkers of vascular health and disease is the isolation, characterization and enumeration of these submicron vesicles. A central feature of this dissertation was the development of flow cytometry protocols to accurately quantify microparticles, their cellular origin and, in some cases, their stimulus for release. These technically challenging approaches were conducted in both biologic samples (plasma) and culture media. Studies associated with this dissertation included: 1) determining whether circulating concentrations of endothelial cell-derived microparticles (EMPs) differ in middle-aged men compared with women; 2) determining, in vitro, whether high glucose (in the diabetic range) induces microparticle release from endothelial cells and, if so, whether high glucose-derived EMPs effect endothelial cell surface expression of key adhesion molecules involved in atherogenesis; and 3) determining whether circulating microparticles from various cell types are elevated in overweight and obese adults; if so, whether elevations in circulating microparticles are a potential biomarker of endothelial dysfunction; and if regular aerobic exercise affects circulating microparticles in overweight and obese adults. The results of these studies demonstrate, for the first time, that: 1) circulating concentrations of activation- and apoptosis-derived EMPs do not differ between middle-aged men and women; 2) high glucose stimulates marked increase in EMPs in addition these EMPs significantly increase the expression of E-selectin, ICAM-1, VCAM-1 and PECAM-1 on the surface of endothelial cells; and 3) circulating levels of EMPs, platelet-, monocyte- and leukocyte-derived microparticles are significantly higher in overweight/obese compared with normal weight adults. In addition, circulating microparticles (EMPs, PMPs and MMPs) are inversely related to endothelial vasodilator function; and regular aerobic exercise training, independent of weight loss, reduces circulating levels of these microparticles in previously sedentary overweight/obese adults.

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