Atheroprotective Signaling Mechanisms Activated by Steady Laminar Flow in Endothelial Cells

Abstract

Many studies of the human vascular tree have shown that atherosclerosis develops at an early age, with areas of the posterior aorta and branch sites showing the earliest fatty streaks. Closer analysis of the branch points showed that the flow dividers, regions of high shear stress with laminar flow, were relatively protected from fatty streak formation. In contrast, there was a predilection for atherosclerosis at the curvatures and lateral walls of branch points.1 These are regions where disturbed flow occurs; importantly, when the time-averaged shear stress is low, the spatial shear stress gradient is very high.1,2 Both monocyte adhesion and endothelial cell (EC) apoptosis also are highest in these areas.3–6 Recently, Cheng et al7 developed a vascular occluder that induced 3 different regions of altered flow: low, high, and low with oscillatory flow. They observed that lesions always developed in regions of low compared with high shear stress. However, the low shear stress was more likely to develop larger lesions with more lipids, expression of inflammatory mediators, and matrix metalloprotease activity than oscillatory flow. When viewed in concert with a study that showed that regions of low shear stress already had a greater number of inflammatory cells resident in the artery wall as a result of increased trafficking,8 it is clear that low flow is proinflammatory and atherogenic. More sophisticated 3-dimensional analysis of flow patterns in human carotid bifurcations has identified prototypic arterial waveforms, “atheroprone” and “atheroprotective,” representing the wall shear stresses in the carotid sinus, which is susceptible to atherosclerotic lesion development, and the distal internal carotid artery, which is resistant.9 Characteristics of the atheroprone waveform include a high oscillatory shear index (≈0.45) and low time-averaged shear stress amplitude (≈0 dyne/cm2). Thus, both the amplitude and flow pattern are key determinants of …