Endothelial function is influenced by a variety of factors, including shear stress direction and magnitude. Whereas improvements in endothelial function have mostly been attributed to increased anterograde flow, the results of many interventional models in humans suggest that enhancing blood flow in both anterograde and retrograde directions to create a high shear stress oscillatory stimulus may be optimal for improving endothelial function. Well-controlled studies are necessary to further this theory. The purposes of this study were to determine the brachial artery acute shear stress and endothelial function responses to (1) passive heat stress (HEAT), (2) ECG-gated cuff compressions (CUFF), and (3) ECG-gated rhythmic handgrip exercise (HGEX); and (4) to determine if there is a relationship between the degree of shear stress oscillation and endothelial function, regardless of the stimulus applied. We hypothesized that (1) HEAT would increase anterograde shear stress and decrease retrograde shear stress, leading to an unpredictable change in endothelial function; (2) CUFF would increase both anterograde and retrograde shear stress, leading to an increase in endothelial function; (3) HGEX would increase anterograde and retrograde shear stress and exercise metabolites, leading to an increase in endothelial function; and (4) the change in oscillatory shear index would be positively associated with the change in flow-mediated dilation, such that an increment increase in the degree of shear stress oscillation would be accompanied by a proportional improvement in endothelial function. In separate visits, 10 young healthy males (22±3 years) underwent 10 minutes of unilateral HEAT, CUFF, or HGEX on the left arm (EXP), while the right arm served as a within-subject time control (CON). Non-invasive finger plethysmography was used to measure heart rate (HR) and blood pressure (BP) throughout the testing sessions. Ultrasonography was used to obtain measures of blood velocity and arterial diameter from the brachial artery of both limbs throughout the interventions. Anterograde and retrograde shear stress (SS) and oscillatory shear index (OSI) were calculated at baseline and during each intervention to assess the blood flow pattern changes. Endothelial function was assessed before and after each intervention, in both limbs simultaneously using a flow-mediated dilation (FMD) test. HEAT increased HR during the intervention (P < 0.05), mean BP and diastolic BP after the intervention (P < 0.05), anterograde SS in EXP (rest: 15.2 ± 2.9 vs. HEAT: 29.8 ± 8.5 dynes/cm2, P < 0.05), and FMD% in both limbs (P = 0.000). CUFF did not change HR or BP, increased anterograde (rest: 17.9 ± 4.1 vs. CUFF: 43.0 ± 12.4 dynes/cm2, P < 0.05) and retrograde (rest: -3.1 ± 2.5 vs. CUFF: -22.7 ± 6.0 dynes/cm2, P < 0.05) SS in EXP, but did not change FMD% in either limb (P = 0.248). HGEX increased HR during the intervention (P < 0.05), mean BP during and after the intervention (P < 0.05), anterograde SS in EXP (rest: 18.7 ± 5.9 vs. HGEX: 56.4 ± 11.5 dynes/cm2, P < 0.05), and FMD% in both limbs (P = 0.001). These findings suggest that an anterograde-dominant shear stress stimulus may be effective at improving endothelial function, but the confounding effect of sympathetic nervous system activation may play a more dominant role in the acute control response for shorter duration interventions such as the ones explored in this study. / Thesis / Master of Science (MSc) / It has been well established that the pattern of blood flow can impact arterial function, but the nuances of this relationship remain unclear. Through the use of heating, cuff compression, and exercise, this study sought to determine the optimal shear stress pattern to see beneficial changes in arterial function in the arm of young healthy males. Our results show many real life interventions alter not only the shear stress pattern in the artery, but also involve other systems like the brain and muscle that are crucial to maintaining the body’s physiological balance. It is clear that arterial function is regulated through a variety of different mechanisms, and that the changes we observe will depend on the parameters (e.g. duration, intensity, timing of assessment) of the applied stimulus. More specifically, isolating study designs should be constructed to determine the individual contributions of different human body systems to the arterial regulatory response.

Introduction: Vascular injury is the crucial initiating event in atherosclerosis and is universal following percutaneous coronary intervention. The cellular response to this injury largely determines vessel outcome. Endothelial progenitor cells (EPCs) and their progeny, late outgrowth endothelial cells (EOCs) are thought to play an important role in this process and characterising this role would be valuable in better understanding vascular injury and repair. Methods: The radial artery in the context of transradial cardiac catheterisation was examined as a model of vascular injury with characterisation of structural injury, longitudinal function and EPC populations. To examine the role of late outgrowth endothelial cells a method for GMP-compliant cell culture and labelling with F18Fluorodeoxyglucose was developed with a view to conducting a cell-tracking study of human administration. Results: Radial artery function was reduced following transradial cardiac catheterisation with recovery over a period of three months. There was no correlation between recovery of arterial function and EPC populations as defined by conventional surface markers. A research grade protocol for EOC culture was successfully translated to a GMP-compliant process producing a viable, phenotypically homogeneous EOC product. Cells were successfully labelled with F18Fluorodeoxyglucose and whilst proliferation was reduced, acute viability and function were not compromised. Conclusion: The radial artery in the context of transradial cardiac catheterisation is a useful model of vascular injury and repair although recovery of vascular function does not appear to be influenced by EPC populations. GMP-compliant culture and labelling of EOCs is feasible and will allow examination of the physiology of these cells in vivo in man.