Atherosclerosis is a chronic inflammatory disease of arterial blood vessels, characterized by deposition of lipoproteins in the arterial wall. Atherosclerotic plaques form preferentially in distinct regions of the vasculature such as branch points, curvatures and bifurcations, suggesting that local hemodynamic forces may contribute to disease susceptibility. Shear stress imparted on endothelial cells (ECs) by the flowing blood has been shown to modulate gene expression and remodelling of the artery. In this thesis, an in vitro model was established to recreate the contrasting environments found in atherosclerosis-prone and atherosclerosis-resistant regions of the vasculature to demonstrate a direct causal-relationship between shear stress and expression of endothelial nitric oxide synthase (eNOS) and p65 in ECs. In vitro assessment of cell shape and expression patterns of these anti- and atherogenic genes demonstrated that shear stress can induce cell morphology and gene expression patterns that are similar to ECs in atherosclerosis-prone and atherosclerosis-resistant regions of the mouse vasculature. Regulation of eNOS transcription by shear stress was demonstrated using a transgenic mouse model and in vitro heterogeneous nuclear RNA (hnRNA) quantification. Similar to ECs in atherosclerosis-prone regions, epithelial cells lining the small intestine lumen express high levels of p65. To investigate the effects of p65 expression levels on constitutive and tumour necrosis factor α (TNFα)-induced nuclear factor-κB (NF-κB) signalling, p65 expression was suppressed in HeLa cells by RNA interference. Lower p65 expression resulted in reduced TNFα-induced expression of NF-κB target genes, including many subunits of inhibitor of nuclear factor κB (IκB), demonstrating modulation of NF-κB priming by p65 expression levels. Suppression of p65 also affected constitutive expression levels of IκB, and resulted in re-setting of the NF-κB/IκB equilibrium. Experiments using inhibitors of canonical NF-κB signalling found that basal expression of NF-κB components is independent of nuclear factor κB kinase β (IKKβ) activity and proteasome-mediated degradation of IκBα. Together, these studies elucidate the mechanism of flow-mediated gene regulation and the effect of resulting changes in p65 expression on NF-κB signalling.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.

Thesis (M.A.)--West Virginia University, 1998. / Title from document title page. Document formatted into pages; contains viii, 101 p. : ill. Vita. Includes abstract. Includes bibliographical references (p. 53-60).

Thesis (M.S.)--Ohio University, November, 2004. / Includes bibliographical references (p. 83-90)

Thesis (M. Med. Sc.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 53-63).

Thesis (Ph.D.)--Biomedical Engineering, Georgia Institute of Technology, 2009. / Committee Chair: Giddens, Don; Committee Member: Heffron, Thomas; Committee Member: Martin, Diego; Committee Member: Oshinski, John; Committee Member: Vito, Raymond.

Thesis (M.Med.Sc.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 53-63). Also available in print.

Thesis (doctoral)--Københavns Universitet. / Summary in Danish. Bibliography: p. 44-48.

Thesis (M.S.)--Ohio University, November, 2004. / Title from PDF t.p. Includes bibliographical references (p. 83-90)

Orientador: Cezinande de Meira / Coorientador: José Nicolau Prospero Puoli Filho / Banca: João Carlos Pinheiro Ferreira / Banca: Luciano Andrade Silva / Resumo: O útero, por ser o local de desenvolvimento do concepto, necessita de um exame criterioso, principalmente na avaliação e seleção de receptoras de embrião. A ultrassonografia Doppler permite uma avaliação não invasiva e em tempo real da hemodinâmica uterina. Em éguas, assim como em outras espécies, o útero sofre alterações fisiológicas ao longo do ciclo estral, reguladas pelos hormônios esteroidais, estrógeno (E2) e progesterona (P4), e por complexas interações entre fatores de crescimento locais secretados pelo útero. O objetivo do presente estudo foi caracterizar a hemodinâmica uterina de éguas não gestantes, ao longo do ciclo estral, por meio da avaliação ultrassonográfica Doppler de vasos de pequeno calibre, presentes no endométrio, miométrio e mesométrio e correlacioná-la às concentrações plasmáticas dos hormônios esteroidais. Para tanto, 12 éguas não gestantes foram acompanhadas diariamente, durante o intervalo interovulatório, para avaliação do edema e da perfusão vascular uterina. Amostras de sangue foram coletadas diariamente para análise de E2 e P4, por radioimunoensaio. A hemodinâmica uterina apresentou um padrão ondular durante o ciclo estral, com uma diminuição da irrigação no dia da ovulação e no final do diestro, e um aumento no início do diestro e no estro. As concentrações plasmáticas de P4 e de E2 apresentaram correlação negativa e positiva, respectivamente, com a perfusão vascular uterina apenas durante o estro. É muito provável que os hormônios esteroidais estejam envolvidos na regulação da perfusão vascular uterina durante o ciclo estral. No entanto, há diversos fatores mediadores envolvidos neste processo, como a expressão de seus receptores e interações hormonais, que ainda precisam ser explorados / Abstract: The uterus as the site of the conceptus development needs judicious examination, mainly for evaluation and selection of recipient mares. The Doppler ultrasound enables noninvasive evaluation in real-time of uterine hemodynamics. In mares, and also in other species, the uterus suffers physiological alterations during the estrous cycle, regulated by estrogen (E2) and progesterone (P4) hormones, and by complex interactions among local growth factors secreted by the uterus. The aim of this study was to characterize uterine hemodynamics of nonpregnant mares during the estrous cycle using Doppler ultrasonographic analysis in small vessels of the endometrium, myometrium and mesometrium, and correlate it to plasma concentrations of steroid hormones. For that purpose, 12 nonpregnant mares were daily followed, during interovulatory interval for evaluation of uterine edema and vascular perfusion. Blood samples were daily collected for analysis of plasma concentrations of steroid hormones using the radioimmunoassay technique. The uterine hemodynamics presented a wave shaped profile throughout the estrous cycle, with a decrease in the day of ovulation and last diestrous, and an increase in early diestrous and estrous. Negative and positive correlation between P4 and E2 plasma concentrations and uterine vascular perfusion, respectively, was found only during the estrous. The steroid hormones are probably involved in the uterine vascular perfusion regulation during the estrous cycle. However, there are also many mediated factors associated, such as expression of hormone receptors and hormonal interactions which still need to be investigated / Mestre