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This study investigated the expression and activity of tissue transglutaminase (tTG) in human umbilical vein endothelial cells (HUVEC) and vessel wall. tTG was located in the SMC and sub-endothelium of normal vessels. Cross-linking activity was also in this area. Vessels with atherosclerotic plaque showed increased staining for tTG and cross-links. Positive staining for tTG was located in the SMC, neointima, macrophages and the fibrous cap. Most cross-linking activity was observed in the fibrous cap, and cross-linking was observed around macrophages and smooth muscle cells. Cross-linking activity was also observed with incorporation of a labelled cross-linking substrate into vessel sections. Free tTG could be extracted from the vessel wall. HUVEC expressed 10 g tTG/mg total protein. tTG was detected in cell lysate and extracellular matrix, but not in the culture supernatant. Thrombin up-regulated tTG expression at both the mRNA and protein level. Optimal up-regulation was at a thrombin concentration of 1 U/ml The up-regulation by thrombin was dependent on thrombin activity, and was mediated through the thrombin receptor, protease-activated receptor 1 (PAR-1). Cross-linking activity was also increased after thrombin treatment, measured with a microtitre plate assay and an in situ assay. The specific activity of tTG increased after thrombin treatment. Thrombin treatment increased the level of tTG in the HUVEC ECM. Treatment of HUVEC with PMA reduced the expression of tTG mRNA, reduced the level of tTG protein, but increased the tTG cross-linking activity compared to untreated cells.

Kai Hong Kwok. / Thesis submitted in: December 1997. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 90-98). / Abstract also in Chinese. / Chapter Chapter 1 --- Introduction / Chapter 1.1. --- Classification of β-adrenoceptor in cardiovascular system --- p.1 / Chapter 1.2. --- Vasodilator effects of β-adrenoceptor-agonists and their mechanisms --- p.4 / Chapter 1.3. --- Role of endothelium in β-adrenoceptor-mediated vasodilation --- p.7 / Chapter 1.4. --- Role of K+ channels in β-adrenoceptor-mediated relaxation --- p.11 / Chapter 1.5. --- Other aspect regarding the vascular response to stimulation of B-adrenoceptor --- p.15 / Chapter 1.6. --- Clinical aspect of B-adrenoceptor agents --- p.15 / Chapter Chapter 2 --- Methods and Materials / Chapter 2.1. --- Tissue Preparation --- p.19 / Chapter 2.1.1. --- Preparation of the isolated rat mesenteric artery --- p.19 / Chapter 2.1.2. --- Removal of the functional endothelium --- p.19 / Chapter 2.1.3. --- Organ bath set-up --- p.20 / Chapter 2.1.4. --- Length-tension relationship and an optimal resting tension --- p.22 / Chapter 2.2. --- Experimental Procedure --- p.22 / Chapter 2.2.1. --- Relaxant effects of the B-adrenoceptor agonists --- p.24 / Chapter 2.2.2. --- Effects of putative K+ channel blockers --- p.24 / Chapter 2.2.3. --- Effects of inhibitors of nitric oxide activity --- p.25 / Chapter 2.2.4. --- Effect of indomethacin --- p.25 / Chapter 2.2.5. --- "Effects of K+ channel opener, nitric oxide donor and forskolin" --- p.26 / Chapter 2.3. --- Chemicals and Solutions --- p.26 / Chapter 2.3.1. --- Chemicals and drugs --- p.26 / Chapter 2.3.2. --- Preparation of drug stock solutions --- p.26 / Chapter 2.3.3. --- Solutions --- p.28 / Chapter 2.4. --- Statistical Analysis --- p.28 / Chapter Chapter 3 --- Results / Chapter 3.1. --- Relaxant Effect of Isoprenaline --- p.29 / Chapter 3.1.1. --- Relaxant effect of isoprenaline --- p.29 / Chapter 3.1.2. --- Effects of inhibitors of nitric oxide activity --- p.29 / Chapter 3.1.3. --- Effect of charybdotoxin on the vasorelaxant response to isoprenaline --- p.32 / Chapter 3.1.4. --- Effect of glibenclamide on the vasorelaxant response to isoprenaline --- p.32 / Chapter 3.1.5. --- Effect of TPA+ on isoprenaline-induced relaxation --- p.36 / Chapter 3.1.6. --- Effect of TPA+ in the presence of iberiotoxin or glibenclamide --- p.36 / Chapter 3.1.7. --- Effect of Ba2+ on the vasorelaxant effect of isoprenaline --- p.41 / Chapter 3.1.8. --- Effect of raising extracellular K+ on isoprenaline-mediated relaxation --- p.41 / Chapter 3.2. --- Relaxant Effect of Dobutamine --- p.44 / Chapter 3.2.1. --- Effects of inhibitors of endothelium-derived factors on the relaxant effect of dobutamine --- p.44 / Chapter 3.2.2. --- Antagonism of the effect of dobutamine by β1-adrenoceptor antagonist --- p.44 / Chapter 3.2.3. --- Effects of putative Kca channel blockers on the relaxant effect of dobutamine --- p.51 / Chapter 3.2.4. --- Effect of TPA+ on the relaxant effect of dobutamine --- p.55 / Chapter 3.2.5. --- Effect of raising extracellular K+ on the relaxant effect of dobutamine --- p.55 / Chapter 3.3. --- Relaxant Effect of Fenoterol --- p.57 / Chapter 3.3.1. --- Effect of inhibitors of nitric oxide activity on the relaxant effect of fenoterol --- p.57 / Chapter 3.3.2. --- Effect of charybdotoxin on the relaxant effect of fenoterol --- p.57 / Chapter 3.3.3. --- Effect of TPA+ on the relaxant effect of fenoterol --- p.64 / Chapter 3.3.4. --- Effect of glibenclamide on the relaxant effect of fenoterol --- p.64 / Chapter 3.3.5. --- Effect of raising extracellular K+ on fenoterol-mediated relaxation --- p.64 / Chapter 3.4. --- Effects of cAMP- and cGMP-elevating agents --- p.69 / Chapter 3.4.1. --- Effects of inhibitors of endothelium-derived factors on the relaxation induced by nitroprusside and forskolin --- p.69 / Chapter 3.4.2 --- Effect of charybdotoxin on relaxant effect of forskolin --- p.69 / Chapter 3.4.3 --- Effect of Ba2+ on the vasorelaxant effect of forskolin --- p.76 / Chapter 3.4.4 --- Effect of TPA+ on the relaxant effect of forskolin --- p.76 / Chapter 3.4.5 --- Effect of glibenclamide on the relaxant effects of forskolin and cromakalim --- p.76 / Chapter Chapter 4 --- Discussion / Chapter 4.1. --- Effect of Isoprenaline and Fenoterol --- p.77 / Chapter 4.2. --- Effect of Dobutamine --- p.83 / Chapter 4.3. --- Conclusion --- p.88 / References --- p.90 / Publications --- p.98

"This thesis presents an ultrasound technique for measuring the absolute integrated backscatter (IBS) of arterial wall structures through an intervening inhomogeneous soft tissue layer. The aberrating effect of this tissue layer is minimized by normalizing the measured IBS from the wall region of interest with the IBS from an adjacent range cell in blood. The technique may become a tool to differentiate between stable and vulnerable plaques in the carotid artery."

Severe stenosis may cause critical flow conditions related to artery collapse, plaque cap rupture which leads directly to stroke and heart attack. In this paper, a nonlinear viscoelastic model and a numerical method are introduced to study dynamic behaviors of the tube wall and viscous flow through a viscoelastic tube with a stenosis simulating blood flow in human carotid arteries. The Mooney-Rivlin material model is used to derive a nonlinear viscoelastic thin-wall model for the stenotic viscoelastic tube wall. The mechanical parameters in the Mooney-Rivlin model are calculated from experimental measurements. Incompressible Navier-Stokes equations in the Arbitrary Lagrangian-Eulerian formulation are used as the governing equation for the fluid flow. Interactions between fluid flow and the viscoelastic axisymmetric tube wall are handled by an incremental boundary iteration method. A Generalized Finite Differences Method (GFD) is used to solve the fluid model. The Fourth-Order Runge-Kutta method is used to deal with the viscoelastic wall model where the viscoelastic parameter is adjusted to match experimental measurements. Our result shows that viscoelasticity of tube wall causes considerable phase lag between the tube radius and input pressure. Severe stenosis causes cyclic pressure changes at the throat of the stenosis, cyclic tube compression and expansions, and shear stress change directions in the region just distal to stenosis under unsteady conditions. Results from our nonlinear viscoelastic wall model are compared with results from previous elastic wall model and experimental data. Clear improvements of our viscoelastic model over previous elastic model were found in simulating the phase lag between the pressure and wall motion as observed in experiments. Numerical solutions are compared with both stationary and dynamic experimental results. Mooney-Rivlin model with proper parameters fits the non-linear experimental stress-strain relationship of wall very well. The phase lags of tube wall motion, flow rate variations with respect to the imposed pulsating pressure are simulated well by choosing the viscoelastic parameter properly. Agreement between numerical results and experimental results is improved over the previous elastic model.

A German pathologist first described defects in the elastic tissues of human arteries over one hundred years ago. Much evidence now supports the involvement of these elastic tissue defects (ETDs) in the initiation and progression of atherosclerosis, although this association is not well accepted. Recent research has determined that the migration of medial smooth muscle cells into the intima (and therefore the start of the atherosclerotic process) is initiated in an attempt to repair these defects and in addition, that there is a correlation between the extent of intimal thickening and the degree of elastic tissue disruption. The Brown Norway (BN) strain appears to have an increased predilection, having a significantly greater incidence of ETDs within the caudal and renal arteries and the abdominal aorta compared with other rat strains. These defects appear morphologically identical to those observed in the arteries of young humans. The purpose of this study was to determine the magnitude of the genetic and environmental components in the formation of these ETDs in the aorta. Previous studies have demonstrated that the spontaneous formation of elastic tissue defects in the abdominal aorta of the Brown Noway rat is a genetically inherited phenotype, passed from parent to offspring in an autosomal dominant manner. Following crossbreeding of the BN rat with four other strains (two hypertensive and two normotensive) it was determined that, although the inheritance mode of the ETD phenotype followed an autosomal dominant pattern, the expression or penetrance of this phenotype was reduced in F₁ all crossbred groups. Moreover, the early postnatal growth profile of the F₁ pups appeared to be differentially associated with defect formation. To further examine the relationship between aortic ETDs and birthweight, a well-studied model of in utero growth restriction was investigated in the BN rat. On day 18 of a 23-day gestation the uterine arteries were ligated, which resulted in offspring that were 14% smaller than un-operated control pups. This short-term insult resulted in significantly increased numbers of ETDs in growth-restricted animals at 8 weeks of age, an effect that was also observed in 16-week old males. The effect of in utero growth restriction on ETDs in the guinea pig and ApoE knockout mouse was also examined, to determine if ETDs (and subsequent early atherosclerotic events) may be influenced by the exposure to a growth-restricting event in utero. Despite this work leading to the novel characterisation of ETDs in the guinea pig aorta, the growth restricting surgery resulted in poor maternal and pup outcomes, which limited the conclusions that could be drawn from these studies. Furthermore, microarray techniques were employed to examine changes in aortic gene expression following growth restriction, by comparing amplified mRNA extracts from 8-week old growth restricted BN pup aortas with extracts from a group of average birthweight, un-operated BN pups. In combination, these studies propose both genetic inheritance and the in utero environment regulate elastic tissue defect phenotype, which in turn potentially affects the initiation and progression of early atherosclerosis.

Thesis (M. Phil.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 134-145).

Thesis (M.S.)--Rutgers University, 2009. / "Graduate Program in Biomedical Engineering." Includes bibliographical references (p. 60-66).

published_or_final_version / Pharmacology and Pharmacy / Master / Master of Medical Sciences

published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy