Mathematical modeling of arterial endothelial cell responsiveness to flow

Arterial endothelial cell (EC) responsiveness to flow is essential for normal vascular function and plays a role in the development of atherosclerosis. However, mechanisms by which ECs respond to flow remain incompletely understood. EC sensitivity to mechanical stimulation likely occurs via sensing of the mechanical stimulus at the cell surface with subsequent transmission through cytoskeleton to intracellular transduction sites. Recent evidence appears to indicate that the mechanical stimulus is transduced to a chemical stimulus at these sites which subsequently initiates a sequence of biochemical signals. Also, EC responses to flow shear stress adapt perfectly: each response returns to its respective level prior to the onset of flow.; My conceptual framework treats the mechanical stimulus as a force applied to a cellular structure. I model the conversion of this force into the deformation of an EC-surface flow sensor by assuming that it is a standard linear viscoelastic solid (TPMM). Transmission of this deformation signal from the flow sensor through the cytoskeleton to intracellular transduction sites is accomplished by TPMM networks connected in series-parallel configurations. I postulate that the deformation signal is converted into a chemical signal at an intracellular transduction site by inducing a change in its chemical state that I call activation. My notion of a inechanosensitive molecule (MSM) combines a TPMM for deformation and first-order kinetics for the reversible transition between inactive and active states. Coupling is achieved by formulating the phenomenological forward and reverse rate constants as functions of deformation. I develop three control strategies based on the MSM components and implement them via proportional-integral control to ensure perfect adaptation.; For deformations of surface flow sensor and intracellular networks as well as activation of MSM, my results suggest that responses differ based on whether the mechanical forcing stimulus is steady or oscillatory. All three control strategies exhibit perfect adaptation and suggest hypotheses for experiments to elucidate details of EC adaptation to flow. These findings provide insight into the mechanisms by which ECs respond differently to steady versus oscillatory flow and offer a possible rationale for the preferential development of early atherosclerotic lesions in arterial regions of oscillatory flow.