Atherosclerosis is epidemiologically linked and causally related to the presence of ‘risk factors’. Despite their diversity, major risk factors for cardiovascular disease such as hypercholesterolaemia, diabetes, hypertension, physical inactivity, obesity, and tobacco smoking share a common ‘systemic’ mechanism of action, i.e. they act on the entire inner surface of the arterial vascular tree. The cellular and molecular effects of such systemic risk factors, acting through biohumoral mediators, can account for the greater or lesser propensity of different individuals to atherosclerotic vascular disease (the ‘biohumoral’ paradigm).1,2 Atherosclerosis is, however, focal and discrete in location and has clear preferences for certain sites of the vasculature, such as branching points, bifurcations, or the convex side of curved arteries. In addition, some arteries are more prone to atherosclerosis than others (e.g. the carotid artery vs. the subclavian artery, epicardial coronary arteries vs. intramyocardial arteries), and there are preferential locations even within extremely close areas in the same artery, such as in the region of the carotid bifurcation. The ‘site-specific’ location of the process is a golden opportunity, and perhaps a ‘Holy Grail’ for atherosclerosis research. It is usually explained by the action of particular types of shear stress imposed on the arterial wall by flow regimens of the circulating blood.3 In recent years, much progress has been gained in understanding how shear stress is transduced within the artery wall in order to protect from or promote atherogenesis (the ‘biomechanical’ paradigm). Crucial to this understanding is the identification of endothelial responses to shear stress, by which endothelial cells can sense and integrate haemodynamic stimuli and react to them. The arterial endothelium is exposed to three main varieties of haemodynamic forces:4,5 (a) the pressure generated by hydrostatic forces towards the vessel wall; (b) circumferential tensions or stress, resulting from … *Corresponding author. Tel: +39 0871 415 12; fax: +39 0871 402 817. E-mail : rdecater{at}unich.it