Univ., Diss., 2010--Marburg.

Thesis (M. Phil.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 81-93). Also available in print.

Thesis (Ph. D.)--Biomedical Engineering, Georgia Institute of Technology, 2006. / Vito, Raymond, Committee Member ; Nerem, Robert, Committee Chair ; Eskin, Suzanne, Committee Member ; Hanson, Stephen, Committee Member ; Gibbons, Gary, Committee Member.

Thesis (M. S.)--Biomedical Engineering, Georgia Institute of Technology, 2006. / Hanjoong Jo, Ph.D., Committee Chair ; Don P. Giddens, Ph.D., Committee Member ; W. Robert Taylor, M.D., Ph.D., Committee Member ; Ajit Yoganathan, Ph.D., Committee Member.

Thesis (M.S.M.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Endothelial dysfunction is a key modulator of the development of cardiovascular disease. Prior studies in selected samples have suggested that the association of age and vascular function may vary between men and women. To investigate the sex-specific patterns of this association, we utilized non-invasive vascular function testing in the Framingham Heart Study. We measured brachial artery flow-mediated vasodilation, a measure of conduit artery function, and hyperemic flow velocity, a measure of small vessel function, in 6790 participants (49±14 years, 53% women) in the Offspring and Third Generation cohorts. We found evidence of effect modification by sex on the relation of age and flow-mediated dilation (P=0.0001) and the relation of age and hyperemic flow velocity (P<0.0001). Using restricted cubic spine analysis, we observed that the relation of age and flow-mediated dilation was linear in men but nonlinear in women. To further characterize the patterns of vascular aging, we divided the cohort by the median age of 47 years old. In multivariable regression models adjusting for cardiovascular risk factors, there was a greater decline in flow-mediated dilation with increasing age in older as compared to younger women (β=-0.113 95% CI -0.129,-0.098 vs β=-0.046 95%CI -0.064,-0.029, p<0.0001 for difference). Whereas in men the association of age and flow-mediated dilation was similar in old and young men (β=-0.038 95%CI-0.054,-0.021 vs β=-0.038 95%CI-0.061,-0.023, p=0.199 for difference). For reactive hyperemia, we found a greater decline in older participants for both men and women (for young men, β=-0.087 95%CI-0.200,0.027 compared to older men β=-0.776 95%CI-0.883,-0.669 p<0.0001 for difference, for young women β=0.141 95%CI 0.033,0.249 compared to older women, β=-1.054 95%CI-1.156,-0.952, p<0.0001 for difference). In a large, community-based cohort the patterns of association between age and conduit vessel vasodilation differed in men and women with an accelerated decline in women after age 47. Small vessel function declined more rapidly in older participants in both men and women, however the decline was more pronounced in women. Our findings suggest that the process of vascular aging differs based on sex and between conduit vessels and the microcirculation. Further studies are needed to evaluate the longitudinal patterns of vascular aging in men and women. / 2031-01-01

Made available in DSpace on 2014-06-11T19:32:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-07-30Bitstream added on 2014-06-13T19:43:54Z : No. of bitstreams: 1 macedo_mls_dr_botfm_prot.pdf: 3586847 bytes, checksum: 528671d32509cb0d8b738be7fcab29b3 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A hipertensão gestacional está presente em cerca de 10% das gravidezes e ainda é a primeira causa de mortalidade materna no Brasil. O diabetes gestacional complica 7,6% das gestações no Brasil e está associado a esultados perinatais insatisfatórios. Estas complicações cursam com disfunção endotelial e alteração da elasticidade da parede -.vascular. A onometria de aplanação é um método não invasivo, portátil e de fácil aprendizagem que avalia a função endotelial através do estudo da rigidez arterial (perda da elasticidade arterial). Além de avaliar a função endotelial este método oferece estudo indireto de vários parâmentros cardiovasculares centrais. O grande número de informações que este método obtém de maneira não invasiva, faz deste, um instrumento valoroso em pesquisa. Apresenta grande potencial, especialmente, na compreensão dos mecanismos fisiopatológicos que cursam com comprometimento vascular na gravidez. / Gestational hypertension affects 10% of pregnancies and is still the first :ause of maternal mortality in Brazil. Gestational diabetes affects 7,6% of gnancies in Brazil and is associated with an unsatisfactory peri-natal come. These complications are associated to endothelial dysfunction and abnormal elasticity of the arterial wall. Applanation tonometry is a nonvasive, portable and easy learning method that evaluates endothelial nction by the study of arterial stiffness (Iost of arterial elasticity). Beyond e endothelial function evaluation, this method gives, indirectly, several central cardiovascular parameters. The great number of information btained non invasively by this method, makes of this, a valuable instrument in research. It has special potential to help in the comprehension of the mechanisms of those diseases that presents with vascular commitment in pregnancy.

Diet-derived polyphenols are believed to have health benefits on account of their antioxidant properties. Cardiovascular health is considered to be a suitable target for antioxidant therapy because oxidative stress is implicit in atherogenesis – the disease process that underpins heart attacks, ischaemic strokes and peripheral vascular disease. Numerous in vitro, in vivo and clinical studies indicate that polyphenols are protective in cardiovascular disease, but their mechanism of action still remains ambiguous. This thesis describes a wide range of studies to characterise the activity and stability of a key polyphenol, delphinidin, found in widely consumed berries, and ultimately to test the hypothesis that delphinidin, at physiologically relevant concentrations (~1 µM), protects cultured human umbilical vein endothelial cells (HUVECs) against oxidative damage via a mechanism that is independent of direct antioxidant activity. Delphinidin aglycone was found to be unstable in tissue culture medium, in which it decomposed rapidly to simple phenolic compounds, including gallic acid. Electron paramagnetic resonance spectroscopy indicated that, if anything, both delphinidin and gallic acid were pro-oxidant rather than antioxidant. Moreover, high concentrations of both delphinidin and gallic acid induced rapid morphological changes in HUVECs, most notably in the formation of vacuoles or vesicles. Treatment of HUVECs with a range of concentrations (1 nM - 100 µM) of delphinidin and gallic acid showed that high (100 µM) concentrations of both were cytotoxic. However, both agents were found to have a protective effect in cells exposed to oxidative stress when present at concentrations of ~1 µM – too low to be due to direct antioxidant activity. Deeper examination of cells treated with delphinidin and gallic acid indicated that the protective effect was perhaps partially mediated by changes in expression of the intracellular antioxidant, glutathione. Taken together, the results in this thesis suggest that metabolic products of delphinidin might be responsible for the antioxidant effects seen on account of initiating cellular defence responses.

In 1899, the German surgeon Max Wilms hypothesised that different cell types in a variety of childhood kidney cancers were all derived from the mesodermal layer during embryonic development. Nearly a century later, the WT1 gene was identified on the short arm of chromosome 11, and was thought to be inactive in ~20% of nephroblastomas (Wilms’ tumours). The expression of WT1 after birth appears to be restricted to a finite number of tissues, namely, the glomerular podocytes, mesothelium and ~1% of bone marrow cells. Emerging evidence suggests WT1 is required not only for development, but also for tissue homeostasis, regeneration, repair and angiogenesis. Interestingly, WT1 has been implicated in the response to myocardial infarction and tumour angiogenesis, yet its precise role remains unclear. This thesis aims to address the hypothesis that activation of the WT1 gene in the vascular endothelium is essential for physiological and pathophysiological angiogenesis in the adult. In order to assess whether Wt1 was expressed in quiescent endothelial cells (ECs) immunofluorescence was used to analyse a variety of tissues in the adult mouse. Whilst Wt1 was detected in renal podocytes, no endothelial Wt1 expression was discovered in the lung, heart, kidney, spleen and gastrocnemius muscle. In contrast, tissues known to undergo physiological angiogenesis (endometrium and breast) did exhibit Wt1 expression in the vascular endothelium. Moreover, tubular EC outgrowths generated by aortic rings embedded in collagen ex vivo were positive for Wt1. The role of Wt1 in ischaemic angiogenesis was assessed using models of hind-limb and coronary ischaemia in the mouse. Wt1 was detected in ECs and non-vascular cells following ischaemic injury by a combination of immunofluorescence and qualitative real-time polymerase chain reaction (qRT-PCR). Using a time course analysis of these experimental models the chronology of this relationship was demonstrated, alongside the association with key angiogenic factors, such as Vegf. Given the findings in ischaemic tissue the C3(1)/Tag transgenic mammary cancer model was used to test the hypothesis that Wt1 would be upregulated in the tumour vasculature. Endothelial Wt1 was up regulated in these tumours compared to healthy control tissue. This finding was mirrored in a sub-set of aggressive breast cancers, confirming that the results obtained in mice can be translated to humans. Quantitative PCR revealed no association between histopathological grade of the tumours, oestrogen receptor status, and WT1 expression. In order to delineate the cell types involved in vessel formation, Wt1+ cells were sorted using fluorescent activated cell sorting (FACS) from transgenic mice with a green fluorescent protein knocked into the Wt1 locus following sponge implantation. Distinct sub-populations of Wt1+ cells were identified, some of which expressed EC and pericyte markers. Moreover, these Wt1+ sub-populations changed in composition and number over time. These findings were confirmed by genetic fate mapping of Wt1+ cells in this model. Finally, a conditional knockout mouse was generated to allow the selective deletion of Wt1 from vascular ECs in the sponge model of angiogenesis. The results demonstrated that deletion of Wt1 from this cellular compartment led to a dramatic reduction in vessel formation supporting a potential role in regulating angiogenesis. These results support the hypothesis that expression of WT1 in the vascular endothelium contributes to the regulation of angiogenesis in tumours and ischaemic tissue, and provides evidence that selective deletion of the gene inhibits new vessel formation. This suggests that targeting WT1 may have a therapeutic benefit in cancer and could aid regeneration of ischaemic tissues following injury in conditions such as myocardial infarction and critical limb ischaemia.

abstract: In adults, consuming a high-fat meal can induce endothelial dysfunction while exercise may mitigate postprandial endothelial dysfunction. Whether exercise is protective against postprandial endothelial dysfunction in obese youth is unknown. The purpose of this study was to determine if high-intensity interval exercise (HIIE) performed the evening prior to a high-fat meal protects against postprandial endothelial dysfunction in obese adolescent males. Fourteen obese adolescent males (BMI%tile=98.5±0.6; 14.3±1.0yrs) completed the study. After initial screening, participants arrived, fasted at 9:00 in the morning where brachial artery flow-mediated dilation (FMD) was measured using duplex ultrasound after 20min of supine rest (7.0±3.0%) and completed a maximal exercise test on a cycle ergometer (VO2peak=2.6±0.5 L/min). Participants were randomized and completed 2 conditions: a morning high-fat meal challenge with evening prior HIIE (EX+M) or a morning high-fat meal challenge without prior exercise (MO). The EX+M condition included a single HIIE session on a cycle ergometer (8 X 2min at &#8805;90%HRmax, with 2min active recovery between bouts, 42min total) which was performed at 17:00 the evening prior to the meal challenge. In both conditions, a mixed-meal was tailored to participants body weight consisting of 0.7g of fat/kg of body weight consumed (889±95kcal; 65% Fat, 30% CHO). FMD was measured at fasting (>10hrs) and subsequently measured at 2hr and 4hr after high-fat meal consumption. Exercise did not improve fasting FMD (7.5±3.0 vs. 7.4±2.8%, P=0.927; EX+M and MO, respectively). Despite consuming a high-fat meal, FMD was not reduced at 2hr (8.4±3.4 vs. 7.6±3.9%; EX+M and MO, respectively) or 4hr (8.8±3.9 vs. 8.6±4.0%; EX+M and MO, respectively) in either condition and no differences were observed between condition (p(condition*time)=0.928). These observations remained after adjusting for baseline artery diameter and shear rate. We observed that HIIE, the evening prior, had no effect on fasting or postprandial endothelial function when compared with a meal only condition. Future research should examine whether exercise training may be able to improve postprandial endothelial function rather than a single acute bout in obese youth. / Dissertation/Thesis / Ph.D. Exercise and Wellness 2014

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