Impact of stochastic fluctuations in the cell free layer on nitric oxide bioavailability

A plasma stratum (cell free layer or CFL) generated by flowing blood interposed between the red blood cell (RBC) core and the endothelium affects generation, consumption, and transport of nitric oxide (NO) in the microcirculation. CFL width is a principal factor modulating NO diffusion and vessel wall shears stress development, thus significantly affecting NO bioavailability. Since the CFL is bounded by the surface formed by the chaotically moving RBCs and the stationary but spatially non-uniform endothelial surface, its width fluctuates randomly in time and space. We analyze how these stochastic fluctuations affect NO transport in the CFL and NO bioavailability. We show that effects due to random boundaries do not average to zero and lead to an increase of NO bioavailability. Since endothelial production of NO is significantly enhanced by temporal variability of wall shear stress, we posit that stochastic shear stress stimulation of the endothelium yields the baseline continual production of NO by the endothelium. The proposed stochastic formulation captures the natural continuous and microscopic variability, whose amplitude is measurable and is of the scale of cellular dimensions. It provides a realistic model of NO generation and regulation.