Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology

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Abstract

Endothelium lining the cardiovascular system is highly sensitive to hemodynamic shear stresses that act at the vessel luminal surface in the direction of blood flow. Physiological variations of shear stress regulate acute changes in vascular diameter and when sustained induce slow, adaptive, structural-wall remodeling. Both processes are endothelium-dependent and are systemically and regionally compromised by hyperlipidemia, hypertension, diabetes and inflammatory disorders. Shear stress spans a range of spatiotemporal scales and contributes to regional and focal heterogeneity of endothelial gene expression, which is important in vascular pathology. Regions of flow disturbances near arterial branches, bifurcations and curvatures result in complex spatiotemporal shear stresses and their characteristics can predict atherosclerosis susceptibility. Changes in local artery geometry during atherogenesis further modify shear stress characteristics at the endothelium. Intravascular devices can also influence flow-mediated endothelial responses. Endothelial flow-induced responses include a cell-signaling repertoire, collectively known as mechanotransduction, that ranges from instantaneous ion fluxes and biochemical pathways to gene and protein expression. A spatially decentralized mechanism of endothelial mechanotransduction is dominant, in which deformation at the cell surface induced by shear stress is transmitted as cytoskeletal tension changes to sites that are mechanically coupled to the cytoskeleton. A single shear stress mechanotransducer is unlikely to exist; rather, mechanotransduction occurs at multiple subcellular locations.

Key Points

  • Hemodynamic forces, and in particular shear stresses, are regulators of many physiologic and pathologic aspects of endothelial function in the cardiovascular system

  • In vivo and in vitro global endothelial analyses reveal that endothelial phenotypes are heterogeneous over regional and focal length scales, which links flow characteristics to cardiovascular disease protection, susceptibility and development

  • Endothelial responses are sensitive to variations in the characteristics of flow that generate shear stresses; regions with oscillating shear stress and flow reversal correspond with pathologic changes in the artery wall and are a risk factor for atherosclerosis-susceptibility

  • When shear stresses deform the endothelium, a mechanical perturbation is communicated via the cytoskeleton to multiple sites of mechanotransduction, which include cell–matrix adhesion sites, intercellular junctions and the nuclear membrane

  • Endothelial responses that are specific to shear stress offer potential therapeutic pharmacological targets, although a single mechanosensor is unlikely to exist

  • Beneficial systemic effects include maintenance of arterial hemodynamics within normal limits through antihypertensive therapies, regular exercise to promote continuous adaptive remodeling and inhibition of endothelial dysfunction, and (when intervention is required) better design of intravascular devices to optimize flow characteristics

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Figure 1: Flow separations at an arterial branch can predispose or contribute to pathogenesis.
Figure 2: Flow separations at a stenosis that predispose to or contribute to pathogenesis.
Figure 3: Flow separations around a stent strut that predispose to or contribute to pathogenesis.
Figure 4: The decentralized model of endothelial mechanotransduction by shear stress.

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Acknowledgements

The author's research is supported by grants from the National Heart Lung and Blood Institute of the National Institutes of Health.

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Davies, P. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Rev Cardiol 6, 16–26 (2009) doi:10.1038/ncpcardio1397

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