© 2000 American Heart Association, Inc.
Editorials |
Spatial Hemodynamics, the Endothelium, and Focal Atherogenesis
A Cell Cycle Link?
From the Institute for Medicine and Engineering, Department of Pathology and Laboratory Medicine, and the Department of Bioengineering, University of Pennsylvania, Philadelphia.
Correspondence to Peter F. Davies, 1010 Vagelos Research Laboratories, 3340 Smith Walk, Philadelphia, PA 19104-6383. E-mail pfd@pobox.upenn.edu
Key Words: hemodynamics • endothelium • cell cycle • atherosclerosis
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Introduction |
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The characteristics of arterial flow and the hemodynamic forces associated with them have important effects upon endothelial biology1 that have long been implicated in the nonrandom distribution of atherosclerotic lesions.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. Rapidly 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 considerably over short distances of the monolayer such that cells separated by tens of microns consistently experience significantly different hemodynamic environments. This leads to regional heterogeneity of endothelial exposure to flow forces within the same vascular bed4 5 6 as well as cell-to-cell heterogeneity arising from subcellular differences in cell surface geometry.7 Such spatially defined hemodynamic patterns are postulated to underlie the focal origin of atherosclerotic 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
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