Flow, NO, and atherogenesis
JP Cooke - Proceedings of the National Academy of …, 2003 - National Acad Sciences
Proceedings of the National Academy of Sciences, 2003•National Acad Sciences
Atherosclerosis is the major cause of death and disability in the United States, Europe, and
much of Asia. The lesions of atherosclerosis have a nonuniform distribution in the
vasculature and are prone to develop at bends, branches, and bifurcations of the aorta and
its conduit arteries. At these sites in the vasculature laminar flow is disturbed by recirculation,
which resembles an eddy at a river branch. Here the endothelium of the blood vessel is
exposed to reduced and oscillating flow, a hemodynamic condition that produces …
much of Asia. The lesions of atherosclerosis have a nonuniform distribution in the
vasculature and are prone to develop at bends, branches, and bifurcations of the aorta and
its conduit arteries. At these sites in the vasculature laminar flow is disturbed by recirculation,
which resembles an eddy at a river branch. Here the endothelium of the blood vessel is
exposed to reduced and oscillating flow, a hemodynamic condition that produces …
Atherosclerosis is the major cause of death and disability in the United States, Europe, and much of Asia. The lesions of atherosclerosis have a nonuniform distribution in the vasculature and are prone to develop at bends, branches, and bifurcations of the aorta and its conduit arteries. At these sites in the vasculature laminar flow is disturbed by recirculation, which resembles an eddy at a river branch. Here the endothelium of the blood vessel is exposed to reduced and oscillating flow, a hemodynamic condition that produces physicochemical and biological alterations predisposing to atherogenesis (Fig. 1). Recirculation causes an increase in particle residence time, so that lipoproteins and monocytes (the anlagen of atherosclerosis) have greater contact with the endothelium in these regions (1). The endothelium itself is morphologically altered. In relatively straight segments of a conduit vessel, endothelial cells are regularly aligned, each cell with its longitudinal axis oriented in the direction of flow. By contrast, in areas of disturbed flow, the usual orientation of endothelial cells is lost, and the cells become more polygonal in appearance. Intriguingly, endothelial cells at branch points appear to age faster. Endothelial cells exposed to disturbed flow in vitro turn over more rapidly (2). In human iliac arteries, endothelial cells at the bifurcation have shorter telomeres, consistent with a focal acceleration of senescence (3). Senescent human endothelial cells produce less nitric oxide (NO), generate more superoxide anion (O2–), and are more adhesive for monocytes, effects that can be reversed by transfection with the gene encoding telomerase (4).
Laminar flow in a straight segment of the conduit vessel exposes the endothelium to the tractive force of shear stress. Shear stress in a physiological range of 10–40 dynescm2 (1 dyne 10 μN) activates signaling pathways that induce endothelial elaboration of a number of vasoactive factors such as NO, prostacyclin, tissue plasminogen activator, and transforming growth factor ß (5–8). Nitric oxide is paradigmatic of these factors that promote vasodilatation, inhibit adherence of circulating blood elements, and suppress the proliferation and migration of vascular smooth muscle cells (9). In
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