Copy of author's previously published article in pocket on back end-paper. Includes bibliography (leaves 135-185). Aims to characterise the expression of PETA-3 (Platelet Endothelial Tetraspan Antigen-3), CD9, CD63 and ?gb?s1 integrins in normal human tissue ; to determine the subcellular localisation in endothilial cells and platelets ; to investigate protein-protein interactions involving PETA-3 ; and to examine the effects of anti-PETA-3 monoclonial antibodies on platelet and endothilial cell function.

<p>Cerebrovascular disease (CVD) is strongly linked to hypertension and generally occurs later in life than coronary artery disease (CAD). Three quarters of the patients with symptomatic CVD are above 65 years of age. The risk factors are the same for CVD and CAD, but the relative importance of the vascular risk factors differs greatly.</p><p>Genetic causes of stroke are relatively rare. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a hereditary disease which causes CVD in young adults and middle-aged people, with migraine, stroke, psychiatric illness and dementia as clinical manifestations.</p><p>The subject of this thesis is vascular function in stroke and CADASIL. Endothelium-dependent vasodilation (EDV) and arterial stiffness were investigated by different methods in stroke patients and CADASIL patients compared with healthy controls. Venous occlusion plethysmography with intra-arterial acetylcholine was used to evaluate EDV in the forearm resistance vessels. Flow-mediated vasodilation of the brachial artery was used to evaluate EDV in a conduit artery. Stroke patients displayed reduced EDV in resistance vessels compared with a healthy control group, but this reduction was not significant when, in a larger group of stroke patients, adjustments were made for blood pressure, antihypertensive treatment and other risk factors. Flow mediated vasodilation of the brachial artery was reduced in the stroke patients even after adjustment for risk factors. </p><p>Compared with controls, the CADASIL patients showed similar EDV in the conduit artery, but reduced EDV in resistance vessels.</p><p>Arterial compliance was evaluated by augmentation index from pulse wave analysis, by a ratio of cardiac stroke volume and pulse pressure, and by the distensibility of the carotid artery in relation to pulse pressure. Stroke patients and CADASIL patients did not display any significant increase in arterial stiffness when evaluated by these methods. </p>

Epidemiological evidence suggest that exposure to endocrine disrupting compounds (EDCs) is a risk factor for diseases that involves the cardiovascular system but we know little about the mechanisms whereby these compounds can cause injury in the vasculature. The aim of this thesis was to characterize the effects and mechanisms of some EDCs in vascular cells and highly vascularized tissues. Elevated exposure to environmental EDCs is associated with an increased risk for cardiovascular diseases. In vitro studies demonstrated that the environmental EDCs, 1-nitropyrene, PCB126 and bisphenol A, caused distinct changes in primary human endothelial cells. 1‑Nitropyrene induced cell stress and DNA damage, PCB126 caused changes that indicate endothelial dysfunction and vasoconstriction, and BPA induced changes that indicate angiogenesis and vasoconstriction. Further studies demonstrated that long-term exposure of rats to BPA induced changes in rat cardiac tissues in vivo similar to those observed in human endothelial cells in vitro. The type of cellular alterations that were demonstrated is known to play to play a role in cardiovascular disease in humans. These findings suggest that environmental EDCs can cause damage to the human endothelium that may contribute to the development of cardiovascular disease. The beneficial effects of the pharmaceutical EDC tamoxifen in breast cancer treatment are compromised by an increased risk for bleedings, hyperplasia, and cancer in the endometrium. Ex vivo studies identified the glandular and surface epithelia as potential target sites for tamoxifen adduct formation and tamoxifen-induced cell stress the human endometrium. No signs of tamoxifen-induced changes were detected in the blood vessels. The results suggest that bioactivation of tamoxifen and subsequent cell injury in endometrial epithelial cells may play a role for tamoxifen’s side effects in the endometrium. Taken together, this thesis provide evidence that may help understanding how exposure to EDCs can increase the risk for diseases in that involves the cardiovascular system.

Cerebrovascular disease (CVD) is strongly linked to hypertension and generally occurs later in life than coronary artery disease (CAD). Three quarters of the patients with symptomatic CVD are above 65 years of age. The risk factors are the same for CVD and CAD, but the relative importance of the vascular risk factors differs greatly. Genetic causes of stroke are relatively rare. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a hereditary disease which causes CVD in young adults and middle-aged people, with migraine, stroke, psychiatric illness and dementia as clinical manifestations. The subject of this thesis is vascular function in stroke and CADASIL. Endothelium-dependent vasodilation (EDV) and arterial stiffness were investigated by different methods in stroke patients and CADASIL patients compared with healthy controls. Venous occlusion plethysmography with intra-arterial acetylcholine was used to evaluate EDV in the forearm resistance vessels. Flow-mediated vasodilation of the brachial artery was used to evaluate EDV in a conduit artery. Stroke patients displayed reduced EDV in resistance vessels compared with a healthy control group, but this reduction was not significant when, in a larger group of stroke patients, adjustments were made for blood pressure, antihypertensive treatment and other risk factors. Flow mediated vasodilation of the brachial artery was reduced in the stroke patients even after adjustment for risk factors. Compared with controls, the CADASIL patients showed similar EDV in the conduit artery, but reduced EDV in resistance vessels. Arterial compliance was evaluated by augmentation index from pulse wave analysis, by a ratio of cardiac stroke volume and pulse pressure, and by the distensibility of the carotid artery in relation to pulse pressure. Stroke patients and CADASIL patients did not display any significant increase in arterial stiffness when evaluated by these methods.

Atherosclerosis is a systemic disease occurring in specific sections of the cardiovascular tree such as the carotid and the coronary arteries. Previous studies proposed a strong correlation between plaque localization and blood flow patterns in specific sections of the arteries. In order to elucidate cellular mechanisms that contribute to atherosclerosis, standard cone-and-plate devices are widely used in experiments to reproduce in vitro the effect of different hemodynamic conditions on endothelial cells. In this study, a novel computational fluid dynamic (CFD) numerical code based on the immersed boundary method is developed to simulate this microscopic flow field under different geometries and flow conditions. A comprehensive validation of the CFD code is performed. Once validated, the code is used to analyze the flow field in the cone-and-plate device simulating conditions typically employed in endothelial cell experiments. No previous studies have yet been performed on the fluid dynamics of the cone-and-plate device when surfaces representing actual endothelial cell contours are modeled on the plate surface. This represents a great opportunity to correlate the fluid dynamics in the experimental device and the biochemical properties of the cells under specific flow conditions. The challenging aspect of the problem is represented by its different length scales. While the size of the cone-and-plate device is of the order of millimeters, the endothelial cells laying on the plate surface have size of the order of microns. The goal is to obtain a spatial resolution smaller than the height of the single cell. This allows us to investigate the biological features of the endothelial cells under shear stress in different areas of their membrane surface. This feature must be incorporated in the numerical grid, representing a challenging computational problem and is expected to be a major contribution of the research.

Multiple interacting mechanisms control the formation and dissolution of clots to maintain blood in a state of delicate balance. In addition to a myriad of biochemical reactions, rheological factors also play a crucial role in modulating the response of blood to external stimuli. The broad stimuli for clot formation were laid out, more than a century ago, in, what is now referred to as, Virchow’s triad. To date, a comprehensive model for clot formation and dissolution, that takes into account the biochemical, medical and rheological factors, has not been put into place, the existing models emphasizing either one or the other of the factors. In this dissertation, a model is developed for clot formation and dissolution that incorporates many of the relevant crucial factors that have a bearing on the problem. The model, though just a first step towards understanding a complex phenomenon goes further than previous models in integrating the biochemical, medical and rheological factors that come into play. The model is tested in some simple flow situations as part of an attempt to elucidate Virchow’s triad. Extensions to the model, along with detailed numerical studies, will hopefully aid in a clearer understanding of the phenomenon, and in making relevant clinical correlations.

Thesis (M. Med. Sc.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 44-50).

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 182-198). Also available in print.

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 118-145). Also available in print.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences