UMD Theses and Dissertations
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Item REGULATORY EFFECTS OF ACUTE AND CHRONIC ENDURANCE EXERCISE ON NITRIC OXIDE AND REACTIVE OXYGEN SPECIES IN HUMAN CIRCULATING ANGIOGENIC CELLS(2011) Jenkins, Nathan Thomas; Hagberg, James M; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This dissertation research comprised three studies examining the effects of acute and chronic endurance exercise on circulating angiogenic cells (CACs). Because the balance between nitric oxide (NO) and reactive oxygen species (ROS) is a critical aspect of the physiological function/dysfunction of CACs, each study determined the effects of exercise on NO-ROS balance within a variety of CAC types. Study #1 demonstrated that regular endurance exercise is associated with greater basal intracellular NO levels in cultured CACs, and that one mechanism underlying this association was increased NADPH oxidase enzyme activity in the sedentary state. Study #2 suggested an association between a sedentary lifestyle and increased nitro-oxidative stress in freshly-isolated CD34+ progenitor cells. Study #3 demonstrated that prior exercise attenuates high-fat meal induced-increases in mitochondrial-derived intracellular ROS in CD31+ CACs. Overall, it is concluded that acute and chronic endurance exercise enhance intracellular NO and ROS dynamics in CACs.Item Sustained Delivery and Pharmacodynamics of an Integrin Antagonist for Ocular Angiogenesis(2007-11-19) Fu, Yingli; Wang, Nam Sun; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Ocular angiogenesis, or the formation of new blood vessels in the eye, is the leading cause of blindness in a variety of clinical conditions. Success in elucidation of several key steps in angiogenesis cascade has opened a door for anti-angiogenesis therapies. Development of novel therapeutic agents provides effective treatment for ocular disorders. However, treatment of many posterior segment diseases like age-related macular degeneration (AMD) and diabetic retinopathy (DRP) is far from satisfactory due to the limited availability of novel therapeutic drugs and the low efficiency of traditional drug delivery methods. In the present study, we investigated the anti-angiogenic properties of a novel small integrin antagonist, EMD478761, and developed sustained release systems to locally and continuously deliver this compound. In part I, sustained delivery implants were designed and investigation of their anti-angiogenic efficacy, including inhibition and regression, was performed using in vivo chick chorioallantoic membrane (CAM) assay. In part II, laser-induced choroidal neovascularization (CNV) rat model was employed to further examine the angiogenic inhibitory effect of EMD478761 from a sustained release microimplant. And in part III, the pharmacodynamics of EMD478761 was studied to reveal the mechanisms by which EMD478761 inhibited angiogenesis. Results from in vivo CAM assay and CNV rat model demonstrated that EMD478761 inhibited and regressed basic fibroblast growth factor (bFGF)-induced angiogenesis, and suppressed laser-induced CNV via sustained release implants. The pharmacodynamics of this drug was studied to better understand the mechanisms of the drug's action mode in preventing neovascularization. In vitro, EMD478761 inhibited human umbilical vein endothelial cell (HUVEC) proliferation, caused HUVEC detachment in vitronectin-coated surfaces in a time- and dose-dependent manner, and disrupted endothelial cell tube formation on Matrigel. In addition, EMD478761 induced HUVEC apoptosis on vitronectin via caspase-3 activation pathway. In vivo, EMD478761 induced endothelial cell apoptosis within CNV lesions as demonstrated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. In addition, EMD478761 increased the integrin αvβ3 internalization in HUVECs, while it did not affect integrin αvβ3 expression levels after 12 hours treatment. Taken together, these findings demonstrate that sustained delivery of EMD478761 may provide an effective antiangiogenic approach for the treatment of ocular angiogenesis.Item DNA SEQUENCE VARIATION IN THE PROMOTER REGION OF THE VEGF GENE: IMPACTS ON VEGF GENE EXPRESSION AND MAXIMAL OXYGEN CONSUMPTION(2005-07-29) Prior, Steven John; Roth, Stephen M; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Maximal oxygen consumption (Vo2max) is inversely associated with cardiovascular and all-cause mortality and is responsive to aerobic exercise training. A portion of the increase in Vo2max with aerobic exercise training can be attributed to an increase in skeletal muscle capillarity (i.e., angiogenesis), which contributes to increased blood flow and oxygen extraction in working skeletal muscle. One contributing factor to exercise-induced angiogenesis is vascular endothelial growth factor (VEGF), as it is an endothelial cell proliferation and migration factor that is upregulated by acute aerobic exercise. Significant variability has been observed in VEGF protein levels, VEGF gene expression, skeletal muscle capillarity, and Vo2max before and after aerobic exercise training. Additionally, variability is found in the DNA sequence of the gene encoding VEGF. Variation in the VEGF gene has the ability to impact VEGF gene expression and VEGF protein level and because of the relationship between VEGF, angiogenesis, and Vo2max, we hypothesized that variation in the VEGF gene is related to VEGF gene expression in human myoblasts, plasma VEGF level, and Vo2max before and after aerobic exercise training. The present report shows that VEGF promoter region haplotype impacts VEGF gene expression in human myoblasts in vitro. It was also found that VEGF promoter region haplotype was associated with Vo2max in older men and women before and after exercise training in a manner that is consistent with the results of the VEGF gene expression experiments. Additionally, we found that plasma VEGF level was not associated with VEGF promoter region haplotype, nor did plasma VEGF level correlate with baseline Vo2max or the change in Vo2max with aerobic exercise training. To date, we are the first to report that VEGF promoter region haplotype impacts VEGF gene expression in human myoblasts and is associated with Vo2max. These results have potential implications for aerobic exercise training and may also contribute to the understanding of the function of the VEGF promoter region in different cell types. Furthermore, these results may prove relevant in the study of pathological conditions which can be affected by angiogenesis, namely obesity, cancer, coronary artery disease, and peripheral artery disease.