Spatial Hemodynamics, the Endothelium, and Focal Atherogenesis

he characteristics of arterial flow and the hemodynam- ic forces associated with them have important effects upon endothelial biology1 that have long been impli- cated in the nonrandom distribution of atherosclerotic le- sions.2 At branches, curvatures, and bifurcations of large elastic and muscular distributing arteries, separations of the flow streamlines create regions of disturbance that correlate closely with the early appearance of atherosclerosis. Within the regions of flow disturbance, the cardiac cycle imposes complicated spatial patterns of flow that include nonuniform, multidirectional pulsatile forces at variable frequencies. Rap- idly changing gradients of shear stress arising from flow reversals and secondary flows frequently result in lower average levels of shear stress. 3 The endothelial cells at these locations are subject to shear stress forces that vary consid- erably over short distances of the monolayer such that cells separated by tens of microns consistently experience signif- icantly different hemodynamic environments. This leads to regional heterogeneity of endothelial exposure to flow forces within the same vascular bed 4-6 as well as cell-to-cell heterogeneity arising from subcellular differences in cell surface geometry.7 Such spatially defined hemodynamic pat- terns are postulated to underlie the focal origin of atheroscle- rotic lesions by inducing small groups of endothelial cells toward a proatherosclerotic phenotype through differential mechanosignaling, transcription, and protein expression. 8 Nearly 30 years ago, Wright9 conducted the first studies of endothelial cell proliferation in vivo that are now recognized as relevant to endothelial regional heterogeneity. She noted that although the fraction of mitotic endothelial cells is extremely low throughout the arterial tree, there are loci of proliferating cells associated with curvatures and near branch arteries, regions of predictable disturbed flow. The associa- tion of endothelial cell cycle activity with atherosclerotic susceptible regions in animal models has since been further defined,10 and in vitro models of disturbed flow support the in