Atherosclerosis and Calcium Signalling In Endothelial Cells
The focus of this research is to understand and model the effects of arterial geometry on nucleotide and endothelium cellular processes. The project brings together a group of researchers, from a diverse range of backgrounds, in the Departments of Engineering, Mathematics and Biological Science.
Nucleotides and the Endothelium
Adenine nucleotides such as adenosine triphosphate (ATP) and diphosphate (ADP) have been shown to be important modulators of vascular tone (the muscle tension in the arterial wall). These nucleotides react with receptors on the endothelial cells, and control arterial geometry (vasodilation) via the production of Endothelium-derived relaxing factor (EDRF). Nucleotides can be present in flowing blood as a result of the activation of platelets and from vessel wall damage. At the endothelial surface the agonist ATP undergoes degradation via the following reaction mechanism: ATP → ADP → AMP → adenosine, where the latter two have been observed to be in low concentration due to slow reaction rate. The concentration profile of nucleotides at the surface of the endothelial cells is dependent on the velocity profile of the blood which brings ATP from upstream. ATP needs to be continuously transported to the surface of the endothelium in order to regulate responses; this transport to the surface is brought about by convective and diffusive processes. Haemodynamic shear stress, the tangential force exerted on the endothelial cells by the flowing blood, evokes a number of responses by the endothelial cells; in particular it has been demonstrated that endothelial cells respond to fluid shear stress by increasing cytosolic free Ca2+ concentration.
Models in Production
Previously, mathematical models have been developed to evaluate the concentration of nucleotides at the endothelium. Specifically the model used in this research can take any “well behaved” wall shear stress function, which is related to vessel geometry, and evaluate the nucleotide concentration at the endothelium.
The main focus of this research, in terms of nucleotide concentration, is looking at the concentration variation in an arterial bifurcation; this geometry is important as it is known to have numerous effects on the health of the cardiovascular system ie. atheroma occurs preferentially where the wall shear stress is low or spatially vary, which is associated with this geometry.
Numerical models, for similar flow scenarios as the analytical, are also important; these models provide useful comparisons and validation of the analytical model results. Additionally, certain flow scenarios, such as a 2D arterial bifurcation, have wall shear stress functions that cannot to be obtained analytically, so the wall shear stress must be taken from numerical simulations; this can then be used to evaluate nucleotide concentration at the endothelium.