Endovascular transport of blood-borne molecules and their interactions with the vascular wall

The pathological complications of atherosclerosis, namely heart attacks and strokes, are the leading cause of mortality in industrialized countries. The mechanisms governing atherogenesis (the very early stages of atherosclerosis) have not been fully elucidated. A hallmark of early atherosclerosis is dysfunction of the arterial endothelium, the monolayer of cells lining the inner surfaces of blood vessels. A large number of studies over the past two decades have demonstrated that endothelial cells (ECs) exhibit a wide array of flow-induced responses. In the present dissertation, essential issues associated with the role of endovascular transport of blood-borne molecules and their interactions with ECs in mediating flow-induced EC responses have been addressed by numerical simulations. The issues include: (1) the impact of the rheological behavior of blood on the flow field produced by a backward facing step geometry, (2) the transport of the adenine nucleotides ATP and ADP and the reactions of these nucleotides with the EC surface in the backward facing step geometry, and (3) the influence of an undulating EC surface topography on the shear stress and ATP/ADP concentration at the EC surface. The key findings of the research are: (1) the effects of non-Newtonian behavior of blood on the flow field are significant especially within and near the disturbed flow zone immediately downstream of the step, (2) flow separation and recirculation affects the transport behavior of ATP and ADP and leads to significant differences in ATP and ADP concentration at the EC surface between regions within and outside the flow recirculation zone, and (3) the influence of EC surface topography on the concentration of ATP and ADP at the EC surface may be pronounced depending on flow conditions and reaction kinetics of ATP/ADP. These findings suggest that: (1) EC mechanotransduction pathways stimulated by Newtonian and non-Newtonian fluids may be different in regions of flow disturbance, and (2) disturbed and undisturbed flow may affect EC calcium mobilization differently. If confirmed experimentally, the present study may provide a basis for better understanding the involvement of flow disturbance in EC dysfunction and vascular pathogenesis.