Shear stress and the endothelium
Authors: Barbara J. Ballermann, Alan Dardik, Eudora Eng, Ailian Liu
Journal: Kidney International (1998)

Shear stress and the endothelium. Vascular endothelial cells (ECs) in vivo are influenced by two distinct hemodynamic forces: cyclical strain due to vessel wall distention by transmural pressure, and shear stress, the frictional force generated by blood flow. Shear stress acts at the apical cell surface to deform cells in the direction of blood flow; wall distention tends to deform cells in all directions. The shear stress response differs, at least partly, from the cyclical strain response, suggesting that cytoskeletal strain alone cannot explain it. Acute shear stress in vitro elicits rapid cytoskeletal remodeling and activates signaling cascades in ECs, with the consequent acute release of nitric oxide and prostacyclin; activation of transcription factors nuclear factor (NF)κB, c-fos, c-jun and SP-1; and transcriptional activation of genes, including ICAM-1, MCP-1, tissue factor, platelet-derived growth factor-B (PDGF-B), transforming growth factor (TGF)-β1, cyclooxygenase-II, and endothelial nitric oxide synthase (eNOS). This response thus shares similarities with EC responses to inflammatory cytokines. In contrast, ECs adapt to chronic shear stress by structural remodeling and flattening to minimize shear stress. Such cells become very adherent to their substratum and show evidence of differentiation. Increased adhesion following chronic shear stress has been exploited to generate vascular grafts with confluent EC monolayers, retained after implantation in vivo, thus overcoming a major obstacle to endothelialization of vascular prostheses. Shear stress and the endothelium. Vascular endothelial cells (ECs) in vivo are influenced by two distinct hemodynamic forces: cyclical strain due to vessel wall distention by transmural pressure, and shear stress, the frictional force generated by blood flow. Shear stress acts at the apical cell surface to deform cells in the direction of blood flow; wall distention tends to deform cells in all directions. The shear stress response differs, at least partly, from the cyclical strain response, suggesting that cytoskeletal strain alone cannot explain it. Acute shear stress in vitro elicits rapid cytoskeletal remodeling and activates signaling cascades in ECs, with the consequent acute release of nitric oxide and prostacyclin; activation of transcription factors nuclear factor (NF)κB, c-fos, c-jun and SP-1; and transcriptional activation of genes, including ICAM-1, MCP-1, tissue factor, platelet-derived growth factor-B (PDGF-B), transforming growth factor (TGF)-β1, cyclooxygenase-II, and endothelial nitric oxide synthase (eNOS). This response thus shares similarities with EC responses to inflammatory cytokines. In contrast, ECs adapt to chronic shear stress by structural remodeling and flattening to minimize shear stress. Such cells become very adherent to their substratum and show evidence of differentiation. Increased adhesion following chronic shear stress has been exploited to generate vascular grafts with confluent EC monolayers, retained after implantation in vivo, thus overcoming a major obstacle to endothelialization of vascular prostheses. diacylglycerol endothelial cells endothelial nitric oxide synthase endothelin focal adhesion kinase 5-trisphosphate N-terminal Jun kinase mitogen-activated protein kinase nuclear factor κ B nitric oxide platelet-derived growth factor-B protein kinase C phospholipase A2 phospholipase C stress-activated protein kinase transforming growth factor Endothelial cells (ECs) in vivo are influenced by two key hemodynamic forces: transmural pressure gradients and wall shear stress. In blood vessels in vivo, these forces vary in a pulsatile fashion, except in locations where the cardiac pressure curve has been dampened by high upstream resistances. Transmural pressure gradients result in vessel wall distention and development of wall tension, as described by Laplace's law1.Milno W.R. Principles of hemodynamics,.in: Mountcastle V.B. Medical Physiology. Mosby, St. Louis1974: 914Google Scholar: T=ΔP×r where ΔP is the transmural pressure gradient and r is the radius. Wall tension is thus directly proportional to the transmural pressure gradient and vessel diameter. The distensibility of the vessel wall is determined by its thickness, composition, and degree of smooth muscle contraction1.Milno W.R. Principles of hemodynamics,.in: Mountcastle V.B. Medical Physiology. Mosby, St. Louis1974: 914Google Scholar. Because wall tension rises with increasing vessel diameter, for any given transmural pressure gradient, tension is greatest in vessels that are highly distensible. Tension develops in all structural components of the vessel wall, including extracellular connective tissue and the cytoskeleton of constituent cells. Tension is transmitted to the cell cytoskeleton at points of cell-cell and cell-matrix adhesion, where the cytoskeleton connects to adhesion molecules on other cells or to matrix molecules via several transmembrane proteins. In highly distensible vessels, the degree of cell cytoskeletal deformation and tension due to transmural pressure gradients can be very large. Endothelial cells also are subject to the frictional force shear stress generated by blood flowing past their apical surfaces. This force is determined by the mean fluid flow rate, its viscosity, and the physical dimensions of blood vessels. For Newtonian fluids (defined as those for which flow velocity does not alter viscosity) flowing in rigid containers with unvarying internal geometry, uniform velocity gradients develop such that fluid velocity is least at the stationary vessel wall and rises with increasing distance from it. Fluid flow with this characteristic uniform velocity gradient is termed laminar flow because the fluid can be viewed as a series of molecular layers (laminae) slipping past each other with increasing velocity as the center of the container is approached Figure 1. In a uniform, rigid cylinder, shear stress (τ) at the vessel wall can be derived from Poiseuille's law1.Milno W.R. Principles of hemodynamics,.in: Mountcastle V.B. Medical Physiology. Mosby, St. Louis1974: 914Google Scholar as: τ=4Q×η/Π×r3 where Q is the fluid flow rate, and η is the fluid viscosity. If mean flow rate is constant, the greater the resistance to flow, either because of high fluid viscosity or small vessel diameter, the greater the shear stress. Shear stress causes cell deformation (strain), which raises cytoskeletal tension, although the direction of the deformation differs from that produced by transmural pressure gradients Figure 1. In the purest sense, therefore, shear stress and transmural pressure gradients are unrelated forces, each of which cause EC strain. In both cases, there is deformation of cytoskeletal elements, cell membranes, and sites of cell-cell and cell-matrix adhesion with consequent tension development. However, in the case of shear stress, the force on a given cell acts in one direction, whereas stretch due to transmural pressure gradients occurs in all directions. It is also of note that only the ECs, but not vascular smooth muscle cells or pericytes, are exposed to shear stress, whereas all vessel wall components are deformed by transmural pressure gradients. Biological systems depart from the defined conditions mentioned earlier here, as blood is non-Newtonian; that is, blood viscosity tends to decrease with increasing velocity, and vessels are nonuniform, variably distensible containers1.Milno W.R. Principles of hemodynamics,.in: Mountcastle V.B. Medical Physiology. 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The precise mechanisms of mechanical-chemical coupling in ECs exposed to shear stress are not fully understood. Ingber11.Ingber D.E. Tensegrity: The architectural basis of cellular mechanotransduction.Annu Rev Physiol. 1997; 59: 575-599Crossref PubMed Scopus (1254) Google Scholar has reasoned that physical forces are transmitted from the environment to the cell at points where extracellular and intracellular structural elements are interconnected and that mechanical-chemical coupling therefore reflects adaptation to forces that alter tension in cell structural components. Indeed, he has shown that application of stress to integrins, known to be connected to the cell cytoskeleton, results in cell deformation (strain) with secondary tension development, whereas the same stress applied to cell-surface receptors not connected to the cytoskeleton does not alter cytoskeletal tension12.Wang N. Butler J.P. Ingber D.E. 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As is discussed later here, there is considerable evidence that signaling via integrins, which anchor cells to their substratum, and focal adhesion-associated proteins regulates a number of cell signaling cascades. Signaling via integrins may also play a role in the acute shear stress response. In addition, stretch-sensitive Ca2+ channels are activated by shear stress, probably as a result of their deformation by transmitted tension from the plasma membrane and subplasma membrane scaffolding proteins to the channels. The possibility that ECs might express specific mechanosensors at their apical cell surface14.Davies P.F. Robotewskyj A. Griem M.L. Dull R.O. Polacek D.C. Hemodynamic forces and vascular cell communication in arteries.Arch Pathol Lab Med. 1992; 116: 1301-1306PubMed Google Scholar distinct from known cytoskeletal proteins, though attractive, is not supported by experimental data at this time. 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Acute shear stress refers to conditions in which ECs not previously accustomed to shear stress are suddenly exposed to this force with a time frame measured in seconds to hours14.Davies P.F. Robotewskyj A. Griem M.L. Dull R.O. Polacek D.C. Hemodynamic forces and vascular cell communication in arteries.Arch Pathol Lab Med. 1992; 116: 1301-1306PubMed Google Scholar. Chronic shear stress refers to conditions in which ECs are cultured for several days to weeks under the influence of shear stress, with or without superimposed acute alterations in the level of shear stress. The chronic shear stress model more closely approximates conditions in vivo, where ECs are continuously exposed to shear stress with variations in the level of shear stress due to alterations in blood flow rate and vessel wall diameter. In contrast, acute shear stress conditions are only observed in vivo when flow is first initiated through newly formed blood vessels or when blood flow in an established vessel is reinitiated after temporary occlusion. Acute shear stress responses may also mimic, at least in part, in vivo responses of injured or activated endothelium to shear stress. The most rapid responses of ECs to shear stress involve activation of at least two distinct apical ion channels. Olesen et al have reported activation of an inwardly rectifying K+ channel within milliseconds after initiation of shear stress19.Olesen S.P. Clapham D.E. Davies P.F. Haemodynamic shear stress activates a K+ current in vascular endothelial cells.Nature. 1988; 331: 168-170Crossref PubMed Scopus (717) Google Scholar. This K+ channel is Ca2+ activated20.Jacobs E.R. Cheliakine C. Gebremedhin D. Birks E.K. Davies P.F. Harder D.R. 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