Do endothelial cells have “comfort zones” for a range of haemodynamic stresses that lead to different triggers of atherosclerosis at different arterial sites?

The patchy distribution of atherosclerosis within arteries implies the existence of local risk factors that control its development. Many hypotheses suggest a role for haemodynamic wall shear stress (WSS), but there is disagreement about which particular characteristics of WSS correlate spatially with the prevalence of lesions. This review considers why such confusion persists despite much research over many decades. Possibilities include the large changes in lesion prevalence that occur over short distances, the inadequate spatial resolution of methods for measuring near-wall flow, the computational demands of including all relevant factors into numerical simulations of flow, the difficulty of obtaining maps of lesion occurrence and WSS metrics in the same artery, the simplistic ways in which WSS metrics have been defined, and failure to consider mechanical factors other than WSS. A particular focus is the fundamental underlying assumption that a single haemodynamic factor triggers the disease. It may instead be the case that endothelial cells have a "comfort zone" for many different mechanical stresses and express an atherogenic phenotype when exposed to any values of a wide range of metrics that are outside this zone. Preliminary evidence that different arterial regions have different mechanical triggers are presented, underlying reasons that can account for such variability are discussed, implications for endothelial mechanotransduction and downstream events such as increased permeability are outlined, and recommendations are made for how future studies might confirm or refute the "comfort zone" concept.