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Vol. 1 has spine title: Control of vascular sensitivity / Vol. 2 has spine title: Aminergic transmitter disposition. / Includes bibliographical references. / 2 v.(various pagings) : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Two volumes of publications between 1948 and 1990. Volume 1 focusses on the control of vascular sensitivity to catecholamines. Volume 2 focusses on tissues other than blood vessels. / Thesis (D.Sc.)--University of Adelaide, Faculty of Science, 1991

published_or_final_version / Medicine / Master / Doctor of Medicine

Bibliography: leaves 167-198. / xv, 198 leaves : ill, ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The principle aim of the studies was to characterise the responses to 5-Hydroxytryptamine (5-HT) occuring in the aorta of a primate species, the common marmoset. Further aims were to determine whether the 5-HT- induced response of the aorta is representative of the serotonergic responses of other vessels from the marmoset, in particular the coronary artery. Studies were extended to vascular disease states following a high lipid diet and aortic balloon-catheterisation. Results are discussed. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1999

Indiana University-Purdue University Indianapolis (IUPUI) / Neurofibromatosis type 1 (NF1) is a genetic disorder resulting from mutations in the tumor suppressor gene NF1. NF1 encodes the protein neurofibromin, which functions to negatively regulate p21Ras signaling. NF1 has a wide range of clinical manifestations, including vascular disease, which is characterized by neointima formation and subsequent vessel occlusion. Despite numerous clinical observations of NF1 vasculopathy, the pathogenesis of vascular lesion formation remains unclear. To determine the consequence of Nf1 haploinsufficiency in vascular disease, we generated an in vivo model for dissecting vascular lesion formation. In response to mechanical arterial injury, Nf1+/- mice have significantly enhanced neointima formation characterized by an accumulation of vascular smooth muscle cells (VSMCs) and excessive cellular proliferation and Ras activation. Further, using the pharmacological antagonist, imatinib mesylate, we identified that neointima formation in Nf1+/- mice was directly dependent on Ras signaling through either the platelet derived growth factor β receptor (PDGF-βR) and/or the C-kit receptor activation. These observations identify a molecular mechanism of neointima formation given that our group has previously demonstrated that Nf1+/- VSMCs have hyperactive Ras signaling through PDGF-βR activation and Nf1+/- bone marrow derived cells (BMDCs) have increased recruitment and survival in response to C-kit activation compared to WT controls. In order to dissect the cellular contribution to neointima formation, we utilized cre/lox technology and adoptive hematopoietic stem cell transfer techniques to genetically delete one allele of Nf1 in endothelial cells, VSMCs or BMDCs individually to test which cell lineage is predominant in NF1 vasculopathy. Surprisingly, in response to carotid artery injury, heterozygous inactivation of Nf1 in BMDCs alone was necessary and sufficient for neointima formation. Specifically, Nf1 haploinsufficiency in BMDCs resulted in an infiltration of macrophages into the neointima, providing evidence of “vascular inflammation” as factor in NF1 vasculopathy. Further, we demonstrate for the first time that NF1 patients have evidence of chronic inflammation determined by increased concentrations of circulating monocytes and pro-inflammatory cytokines. In sum, we provide genetic and cellular evidence of vascular inflammation in NF1 patients and Nf1+/- mice and provide a framework for understanding the pathogenesis of NF1 vasculopathy and potential therapeutic and diagnostic interventions.

In vitro microphysiological system utilizes engineered tissue constructs from human cells to model functional activity of human tissues or organs in both healthy and diseased state, thereby providing a more accurate drug screening than animal models prior to clinical trials. One essential component of an in vitro microphysiological system is a tissue engineered blood vessel (TEBV) that can accurately recapitulate the functional vasculature in vivo. This thesis first explores two most important considerations to a successful TEBV generation, the cell source and the fabrication method. To engineer a vascular tissue construct, an ideal cell source should demonstrate high availability and accurate vessel functionality. Mesenchymal stem cells (MSC) were explored due to their high availability, proliferation capacity, and capability to deposit adequate extracellular matrix (ECM) for cell sheet formation. Vascular smooth muscle cells (SMC) are the cell components that comprise the medial layer of native blood vessel, and thus optimal for demonstrating equivalent biological functionality. However, SMC are much harder to acquire through biopsy, and they have limited proliferative capacity and quick senescence. Therefore, an alternative cell source for SMC was obtained through direct reprogramming approach involving the induced overexpression of myocardin in more readily available human cell sources. The resulting reprogrammed SMC demonstrated close resemblance to the native SMC in terms of its phenotype, related gene and protein expression levels, and contractile function. Two different fabrication methods, nanopatterned cell sheets and dense collagen hydrogel, were explored to engineer a 1 mm inner diameter blood vessel. The fabricated TEBVs were then compared to that of the native blood vessel and each other in terms of its structure, mechanical properties, and vasoactive function in response to stimuli. After selecting the most optimal cell source and fabrication method for developing a human cell-based TEBV for in vitro microphysiological system, the second part of this thesis assesses the capability of the designed TEBV to model a vascular disease for drug screening purposes. Marfan syndrome was selected as a model vascular disease due to its previous history of contradictory results from the animal models and human clinical trials using losartan, an angiotensin II receptor blocker, in terms of preventing aortic root dilation. TEBV fabricated using reprogrammed SMC from Marfan syndrome patient sample and dense collagen hydrogel showed reduced fibrillin deposition, increased vessel diameter and thickness, and reduced vasoconstriction levels when compared to the wild type TEBV, which is consistent with that observed in native vessels of Marfan syndrome patients. Losartan improved the function of Marfan syndrome TEBV, but still at reduced level when compared to that of the wild type. SB203580, a selective inhibitor of p53 MAPK that has been shown to be a better drug candidate than losartan in recent cell-based studies, showed improved TEBV function comparable to that of the wild type. In overall, this thesis presents a successful development of a highly robust, patient-specific in vitro vascular model. An accurate recapitulation of a drug-induced physiological response in humans can speed up the drug screening process with higher efficiency, and this will eventually increase the chances of successful treatment for patients.

People with diabetes are at a greater risk of burn injuries than those without diabetes. This stems from the epidemiological profiles of the conditions and the effects of morbidities associated with diabetes. Both conditions share some similarities in terms of metabolic alterations and suboptimal immune functions which may result in poor outcomes for patients. For that reason, it is reasonable to deduce that patients with diabetes are a challenging group to manage in burns units. However, this deduction should be taken cautiously because of lack of supporting evidence. Accordingly and after consulting with clinical experts, the research in this portfolio investigated the association between diabetes and burn injuries. In particular, two different aspects of this association were investigated in two individual quantitative and descriptive inquiries. The first was a case note review of patients hospitalised with a principal diagnosis of a foot burn injury in a large tertiary hospital in South Australia from 1999 to 2004. The second study investigated management of diabetes in burns units treating adults. This study is an e-mail survey of clinical leaders of burns units in Australia, New Zealand, Hong Kong and the United Kingdom. The clinical leaders were approached indirectly through key liaison persons in each identified unit. In the first study, outcomes for twelve subjects with and fifty-two without diabetes were described using descriptive and non-parametric statistics. In the second study, descriptive frequencies and content analysis were adopted to analyse twenty-nine responses from seventeen out of thirty burns units which participated in the study. Supporting findings in the literature, the first study showed that burn injuries among subjects with diabetes were mainly resulted from household devices. There were no statistically significant differences between subjects with and without diabetes in terms of size and depth of burn injuries and treatment received. In spite of this, there was a statistically significant association between diabetes and the experience of local post-burn complications and longer duration of hospitalisation. The second study indicated that more than twenty-five percent of the respondents believed that multidisciplinary centres should only occasionally be involved in the process of care. Participants reported that the individual profile of each patient plays a major role in determining the management of diabetes. Additionally, it was found that the insulin sliding scale was commonly used in the management of diabetes in burns units. The association between diabetes and a burn injury is a serious issue in terms of health and cost. This association need be addressed firstly and most importantly at the prevention level; secondly through proper management of both diabetes and burns. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1285462 / Thesis (D.Nurs.)--Population Health and Clinical Practice, 2007.

Common risk factors for CVD such as hyperlipidaemia, hypertriglyceridemia, low HDL-C, obesity, insulin resistance, impaired glucose tolerance, inflammation and hypertension may increase the risk of atherosclerosis through altering vascular function. Modification of dietary intake and weight loss can ameliorate these risk factors and may impede the development of atherosclerosis. CVD risk can be assessed by measurement of both traditional e.g. lipid levels, glucose and blood pressure and novel risk markers of CVD e.g. FMD, levels of adhesion molecules, inflammatory markers and adipokines. Changes in these measurements are used to determine effects, if any, of dietary interventions. The studies in this thesis focus on the relationship between nutrition and vascular function and the effects of modifying dietary composition either with, or without weight loss. The primary hypotheses addressed were that a high saturated fat diet would have adverse effects on markers of CVD risk., that short and long term weight loss would have beneficial effects on these markers, that a conventional low fat, high glycaemic load diet would also have adverse effects on these markers and that weight loss would attenuate the BP response to salt. Six studies were conducted to address these hypotheses. The effects of saturated fat were investigated in chapters 3 and 6. In chapter 3, a high saturated fat diet impaired FMD and increased the level of the adhesion molecule Pselectin compared with a high MUFA, a high PUFA, or a low fat, high glycaemic load diet in weight stability. The high fat, high glycaemic load caused increases of 23-39% in TG and decreases of 10-15% in HDL-C but despite these adverse effects there was no change in FMD. In chapter 6, subjects on a very low carbohydrate/high saturated fat diet lost approximately 1 kg more weight over 8 weeks than those on a conventional low fat diet. While other CVD risk factors, glucose, insulin, E and P-selectin, ICAM-1 and PAI-1 levels all improved FMD did not change in either diet. Reductions in LDL-C and CRP were greater on the conventional diet. The effects of weight loss on CVD risk factors were also investigated in the studies in chapters 4, 5, 7 & 8. In chapter 4, moderate weight loss using 2 different low fat diets resulted in improvements in PAI-1 and sICAM-1 but there was no change in FMD. Similarly in chapter 5 weight loss on a low carbohydrate/low saturated fat diet did not change FMD but there were other benefits including reductions in glucose and insulin, LDL-C, adhesion molecules, VCAM1 and ICAM1. Adiponectin did not change after short term weight loss in either of the studies in chapters 5 or 6. In chapter 7 salt loading increased ambulatory day time BP and this response was not altered by short term moderate weight loss. The long term effects of weight loss were investigated in chapters 5, 7 and 8. In chapter 5, after 52 weeks, there was sustained weight loss of 5% but no change in FMD while adiponectin levels increased and LDL-C and insulin were substantially reduced. In chapter 7 the BP response to salt loading remained unchanged despite weight loss maintenance. Finally in chapter 8 weight loss was predicted by protein intake and there were reductions in CVD risk demonstrated by decreases in insulin, TG and CRP and increases in HDL-C. The studies in this thesis demonstrate that moderate weight loss has beneficial effects on traditional and novel cardiovascular disease risk markers but does not have a beneficial effect on FMD regardless of dietary composition. A high saturated fat diet has detrimental effects on novel CVD risk markers in weight stability but weight loss attenuates this effect. A high saturated fat diet may have detrimental effects on adhesion molecules in weight stability and may attenuate the beneficial effects of weight loss on LDL-C and CRP. Moderate long term weight loss maintenance has beneficial effects on most but not all CVD risk markers. / http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1293779 / Thesis (Ph.D.) -- School of Medicine, 2007

In this study, we investigated the role of Ang II in pathological vascular remodeling. We sought to determine whether the humoral or the mechanical effects of Ang II are the dominant factor driving the remodeling process. The following experimental groups were used: control group (untreated mice), mice treated with an angiotensin receptor blocker (Candesartan, 0.5 mg/kg/day,SQ), an ACE inhibitor (Captopril, 6 mg/kg/day), and a calcium-channel blocker (Amlodipine, 7.5 mg/kg/day). All mice (n=6 per experimental group) were from the C57Bl/6 background. The carotid ligation model was implemented to study the differences in vascular remodeling. Additionally, multiple time points (7-, 14-, and 21-days post-surgery) were used to track the progression of remodeling. In Day-7 analysis, all three treatment groups yielded similar remodeling patterns as evidenced by a significant reduction in neointimal area, medial thickening and hypertrophy compared with the control group. Histomorphometric analysis of carotid sections collected 1mm below the ligation demonstrated that the Amlodipine group had 26% reduction in total vessel area, Candesartan a 36% reduction, and Captopril a 28% reduction (p less than 0.05 in all groups compared with Control), as well as a parallel 38-40% drop in medial thickness. In Day-14 analysis, no significant differences between the Controls and treatment groups were observed, although differences were emerging between the treatment groups. Candesartan was found to reduce the extent of negative remodeling observed between the 7- and 14-day Control data, whereas the Captopril group did not exhibit this trend. All treatment groups exhibited less neointimal formation than Controls, similar to Day-7. By the 21-day time point, the Captopril group underwent positive remodeling, resembling the Candesartan and Amlodipine groups. Although total vessel area was analogous among all groups, neointimal areas were significantly decreased in the treatment groups. Blood pressure plays a pivotal role in the modulation of vascular remodeling in response to mechanical injury. Although intermediate timepoint analysis suggests that humoral aspects of ACE inhibition or angiotensin-receptor blockade yielded unique effects on the overall vessel caliber, upon reaching the late, 21-day time point, the mechanical factors became predominant. These data support the importance of blood pressure control in the attenuation of pathological vascular remodeling.

With each heartbeat, major arteries experience circumferential expansion due to internal pressure changes. This pulsatile force is called cyclic strain and has been implicated in playing a pivotal role in the genetic regulation of vascular physiology and pathology. This dissertation investigates the hypothesis that in human umbilical vein endothelial cells (HUVEC), pathological levels of cyclic strain activate the c-Myc promoter, leading to c-Myc transcription and downstream gene induction. To determine expression and time-dependency of c-Myc in HUVEC, mRNA and protein expression of c-Myc under physiological (6-10% cyclic strain) and pathological conditions (20% cyclic strain) were studied. Both c-Myc mRNA and protein expression increased more than three-fold in HUVEC (P4-P5) cyclically-strained at 20%. This expression occurred in a time-dependent manner, peaking in the 1.5-2 hour range and falling to basal levels by 3 hours. Subsequently, the mechanism of c-Myc transcription was investigated by using specific inhibitors to modulate c-Myc transcriptional activation. These compounds, obtained from the University of Arizona Cancer Center, attenuated cyclic-strain-induced c-Myc transcription by about 50%. Having established this reduction in expression, it was investigated how these effects modulate downstream genes that are regulated by c-Myc. The results indicate that direct targeting of the c-Myc promoter may decrease stretch-induced gene expression of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA) and heat shock protein 60 (HSP60). These findings may help in the development of a novel therapeutic opportunity in vascular diseases.