Impact of Blood Vessel Wall Stiffness and Atherogenic Flow Profiles on Subcellular Signaling

Mechanical signal transduction in endothelial cells leads to the differential expression of genes, reorganization of the cytoskeleton, and altered cellular properties. The signals transduced typically result from the shear forces applied to the cells via blood flow. Endothelial cells maintain a confluent organization in the lining of blood vessels to prevent vascular diseases such as atherosclerosis. Local hemodynamics are linked to the non-uniform distribution of atherosclerotic lesions resulting from disruption of this organization in arteries, while arterial wall stiffness has been linked to the progression of atherosclerosis. It has been suggested that local hemodynamics and stiffness of the extracellular matrix (ECM) influence the forces experienced by subcellular components of endothelial cells. We developed a 3D, multiscale, multi-component computational model of an endothelial cell monolayer to investigate how the flow direction and ECM stiffness affect the transmission of forces within and between endothelial cells. The model includes structural components such as cytoskeleton, nuclei, adherens junctions, focal adhesions, and an ECM. Using this model, we can show the effects of atherogenic conditions (arterial stiffening and disturbed flow) on subcellular structures relative to non-atherogenic conditions (arterial softening and laminar flow). By investigating the effects of differing stiffnesses and flow patterns, we can better visualize what happens inside the cells when there are alterations to their surroundings and what force transmission pathways may be active in subcellular components. The validation of this model will include numerous tests of different parameters to determine that the results are sensible for each test. This model will be valuable to discover new areas of concentration for biological researchers trying to determine the mechanism of mechanical force transmission in endothelial cells and subcellular organelles. It will identify the role of each individual mechanosensor in mechanical force transmission events, which may lead to novel therapies to prevent progression of atherosclerosis