Thesis (M.D.)--University of Hong Kong, 1998. / Includes bibliographical references (leaves 194-207).

Thesis (M.D.)--University of Hong Kong, 1998. / Includes bibliographical references (leaves 194-207) Also available in print.

Thesis (Ph. D.)--University of Canterbury, 2007. / Typescript (photocopy). "17 July 2007." Includes bibliographical references (p. [345]-360). Also available via the World Wide Web.

Bibliography: leaves 152-170.

published_or_final_version / Surgery / Master / Master of Philosophy

Thesis (Ph. D.)--Duke University, 2008. / Includes bibliographical references.

Thesis (M. Phil.)--University of Hong Kong, 1997. / Includes bibliographical references (leaf 90-101).

No description available.

Oxidative stress is associated with development and progression of cardiovascular disease. Angiotensin II produces oxidative stress and endothelial dysfunction, and its actions may be attenuated by the activity of angiotensin converting enzyme type 2 (ACE2) which converts angiotensin II to the vasoprotective peptide angiotensin (1-7). Similarly, increased oxidative stress is associated with aortic valve stenosis in humans and mice. In my thesis studies, I explore mechanisms of modulation and generation of oxidative stress in cerebral arteries and heart valves. First, I tested the hypothesis that ACE2 deficiency increases oxidative stress and vasomotor dysfunction in cerebral arteries, and examined the role of ACE2 in vascular aging. Vasomotor function was assessed in the basilar artery ex vivo of adult and old ACE2 deficient (ACE2-/y) and wild type (WT or ACE2+/y) mice. ACE2 was present, but at relatively low levels in cerebral arteries. Systolic blood pressure was similar in adult and old ACE2-/y and ACE2+/y mice. Maximal dilatation to acetylcholine was impaired in the basilar artery from adult ACE2-/y mice compared to adult ACE2+/y. In old mice, maximal vasodilatation to acetylcholine was impaired in ACE2+/y mice and severely impaired in ACE2-/y mice. The antioxidant tempol improved responses to acetylcholine in adult and old ACE2-/y and ACE2+/y mice. Nitrotyrosine staining in the basilar artery was increased in adult ACE2-/y mice and in old ACE2-/y and ACE2+/y mice relative to adult ACE2+/y, which indicates that oxidative stress was higher in cerebral arteries from ACE2 deficient mice and old mice. Expression of NADPH oxidase subunits Nox2 and p47phox, and of pro-inflammatory molecules Rcan1 and TNF alpha; was increased in cerebral arteries from old ACE2-/y and ACE2+/y mice. Additionally, I tested the hypothesis that serotonin induces oxidative stress in human heart valves, and examined mechanisms by which serotonin may increase reactive oxygen species (ROS). Superoxide (O2.-) was measured in heart valves from explanted human hearts that were not used for transplantation. Superoxide levels (lucigenin-enhanced chemiluminescence) were increased in homogenates of cardiac valves and pulmonary artery after incubation with serotonin. A non-specific inhibitor of flavin-oxidases (DPI), or inhibitors of monoamine oxidase-MAO (tranylcypromine and clorgyline), prevented serotonin-induced increase in O2.-. Dopamine, another MAO substrate which is increased in patients with carcinoid syndrome, also increased superoxide levels in heart valves, and this effect was attenuated by clorgyline. Apocynin did not prevent increases in O2.- during serotonin treatment. Addition of serotonin to recombinant human MAO-A generated superoxide, and this effect was prevented by an MAO inhibitor. In conclusion, I have demonstrated that ACE2 deficiency impairs vasomotor function in cerebral arteries from adult mice and augments endothelial dysfunction during aging. Oxidative stress plays a critical role in cerebrovascular dysfunction induced by ACE2 deficiency and aging. I have also identified a novel mechanism whereby MAO-A can contribute to increased oxidative stress in human heart valves and pulmonary artery exposed to serotonin and dopamine.

Background. Extensive studies have been conducted to simulate blood flow in the human vasculature using nonlinear equations of pulsatile flow in collapsible tube plus a network of vessels to represent the whole vasculature and the cerebral circulation. For non-linear models numerical solutions are obtained for the fluid flow equations. Methods. Equations of fluid motion in collapsible tubes were developed in the presence of gravitational force (Gforce). The Lax-Wendroff and MacCormack methods were used to solve the governing equations and compared both in terms of accuracy, convergence, and computer processing (CPU) time. A modified vasculature of the whole body and the cerebral circulation was developed to obtain a realistic simulation of blood flow under different conditions. The whole body vasculature was used to validate the simulation in terms of input impedance and wave transmission. The cerebral vasculature was used to simulate conditions such as presence of G-force, blockage of Internal Carotid Artery (ICA), and the effects on cerebral blood flow of changes in mean and pulse pressure. Results. The simulation results for zero G-force were in very good agreement with published experimental data as was the simulation of cerebral blood flow. Both numerical methods for solutions of governing equations gave similar results for blood flow simulations but differed in calculation performance and stability depending on levels of G-force. Simulation results for uniform and sinusoidal G-force are also in good agreement with published experimental results, Blood flow was simulated in the presence of a single (left) carotid artery obstruction with varying morphological structures of the Circle of Willis (CoW). This simulation showed significant differences in contralateral blood flow in the presence or absence of communicating arteries in the CoW. It also was able to simulate the decreases in blood flow in the cerebral circulation compartment corresponding to the visual cortex in the presence of G-force. This is consistent with the known loss of vision under increased acceleration. Conclusions. This study has shown that under conditions of gravitational forces physiological changes in blood flow in the systemic and cerebral vasculature can be simulated realistically by solving the one-dimentional fluid flow equations and non-linear vascular properties numerically. The simulation was able to predict changes in blood flow with different configurations and properties of the vascular network.