The importance of the endothelium in the local regulation of blood flow is reflected by its influence on vascular tone by means of vasodilatory responses to many physiological stimuli. Regulatory pathways are affected by mass transport and wall shear stress (WSS), via mechanotransduction mechanisms. In the present work, we review the most relevant computational models that have been proposed to date, and introduce a general framework for modelling the responses of the endothelium to alteration in the flow, with a view to understanding the biomechanical processes involved in the pathways to endothelial dysfunction. Simulations are performed on two different patient-specific stenosed carotid artery geometries to investigate the influence of WSS and mass transport phenomena upon the agonist coupling response at the endothelium. In particular, results presented for two different models of WSS-dependent adenosine-5’-triphosphate (ATP) release reveal that existing paradigms may not account for the conditions encountered in vivo and may therefore not be adequate to model the kinetics of ATP at the endothelium. Copyright © 2013 John Wiley & Sons, Ltd.