Abstract
Early atherosclerotic lesions localize preferentially, in arterial regions exposed to low flow, oscillatory flow, or both; however, the cellular basis of this observation remains to be determined. Atherogenesis involves dysfunction of the vascular endothelium, the cellular monolayer lining the inner surfaces of blood vessels. How low flow, oscillatory flow, or both may lead to endothelial dysfunction remains unknown. Over the past two decades, fluid mechanical shear (or frictional) stress has been shown to intricately regulate the structure and function of vascular endothelial cells (ECs). Furthermore, recent data indicate that beyond being merely responsive to shear stress, ECs are able to distinguish among and respond differently to different types of shear stress. This review focuses on EC differential responses to different types of steady and unsteady shear stress and discusses the implications of these responses for the localization of early atherosclerotic lesions. The mechanisms by which endothelial differential responsiveness to different types of flow may occur are also discussed.
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Caro, C. G., Fitzgerald, J. M., and Schroter, R. C. (1969) Arterial wall shear and distribution of early atheroma in man. Nature 223, 1159–1161.
Nerem, R. M. (1992) Vascular fluid mechanics, the arterial wall, and atherosclerosis. J. Biomech. Eng. 114, 274–282.
Svindland, A. and Walloe, L. (1985) Distribution pattern for sudanophilic plaques in the descending thoracic and proximal abdominal aorta. Atherosclerosis 57, 219–224.
Ross, R., and Glomnset, J. A. (1977) The pathogenesis of atherosclerosis. N. Engl. J. Med. 295, 369–381.
Ross, R. (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801–809.
Langille, B. L., and O'Donnell, F. (1991) Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science 231, 405–407.
Pohl, U., Holtz, J., Busse, R.., and Bassenge, E. (1986) Crucial role of endothelium in the vasodilator response to increased flow in vivo. Hypertension 8, 37–47.
Barakat, A. I. and Davies, P. F. (1998) Mechanisms of shear stress transmission and transduction in endothelial cells. Chest 114, 58S-63S.
Barakat, A. I. (1999) Responsiveness of vascular endothelium to shear stress: potential role of ion channels and cellular cytoskeleton. Int. J. Mol. Med. 4, 323–332.
Davies, P. F. and Tripathi, S. C. (1993) Mechanical stress mechanisms and the cell- an endothelial paradigm. Circ. Res. 72, 239–245.
Davies, P. F. (1995) Flow-mediated endothelial mechanotransduction. Physiol. Rev. 75, 519–560.
Malek, A. M. and Izumo, S. (1994) Molecular aspects of signal transduction of shear stress in endothelial cell J. Hypertension 12, 989–999.
Papadaki, M., and Eskin, S. G. (1997) Effects of fluid shear stress on gene regulation of vascular cells. Biotechnol. Prog. 13, 209–221.
Resnick, N. and Gimbrone, M. A., Jr. (1995) Hemodynamic forces are complex regulators of endothelial gene expression. FASEB J. 9, 874–882.
Traub, O. and Berk, B. C. (1998) Laminar shear stress-mechanisms by which endothelial cells transduce an atheroprotective forces. Arterioscl. Thromb. Vasc. Biol. 18, 677–685.
Asakura, T. and Karino, T. (1990) Flow patterns and spatial distribution of atherosclerotic lesions in human coronary arteries. Circ. Res. 66, 1045–1066.
Barakat, A. I., Karino, T., and Colton, C. K. (1997a) Microcinematographic studies of the flow field in the excised rabbit aorta and its major branches. Biorheology 34, 195–221.
Ku, D. N., Giddens., D. P., Zarins, C. K., and Glagov, S. (1985) Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low and oscillating shear stress. Arteriosclerosis 5, 293–301.
Moore, J. E., Jr., Xu, C., Glagov, S., Zarins, C. K., and Ku, D. N. (1994) Fluid wall shear stress measurements in a model of the human abdominal aorta: oscillatory behavior and relationship to atherosclerosis. Atherosclerosis 110, 225–240.
Perktold, K., Florian, H., Hilbert, D., and Peter, R. (1988) Wall shear stress distribution in the human carotid siphon during pulsatile flow. J. Biomech. 21, 663–671.
Perktold, K., and Rappitsch, G. (1995) Computer simulation of local blood flow and vessel mechanics in a compliant carotid artery bifurcation model. J. Biomech. 28, 845–856.
Chien, S., Usami, S., Taylor, M., Lundberg, J. L., and Gergersem, M. I. (1966) Effects of hematocrit and plasma proteins on human blood rheology at low shear rates. J. Appl. Physiol. 21, 81–87.
Acevedo, A. D., Bowser, S. S., Gerritsen M. E., and Bizios, R. (1993) Morphological and proliferative responses of endothelial cells to hydrostatic pressure: role of fibroblast growth factor. J. Cell. Physiol. 157, 603–614.
Letsou, G. V., Rosales, O., Maitz, S., Vogt, A., and Sumpio, B. E. (1990) Stimulation of adenylate cyclase activity in cultured endothelial cells subjected to cyclic stretch. J. Cardiovasc. Surg., 31, 634–639.
Sumpio, B. E., Banes, A. J., Buckley, M., and Johnson, G. (1987) Alterations in endothelial cell morphology and cytoskeletal protein synthesis during cyclic tensional deformation. J. Vasc. Surg. 7, 130–138.
Sumpio, B. E., Banes, A. J., Link, G. W., and Iba, T. (1990) Modulation of endothelial phenotype by cyclic stretch: inhibition of collagen production J. Surg. Res. 48, 415–420.
Hutchison, K. J., Karpinski, E., Campbell, J. D., and Potemkowski, A. P. (1988) Aortic velocity contours at abdominal branches in anesthetized dogs. J. Biomech. 21, 277–286.
Duncan D. D., Bargeron, C. D., Borchardt, S. E., Deters, O. J., Gearhart, S. A., Mark, F. F., and Friedman, M. H. (1990) The effect of compliance on wall shear in casts of a human aortic bifurcation. J. Biomech. Eng. 112, 183–188.
Kuban, B. D. and Friedman, M. H. (1995) The effect of pulsatile frequency on wall shear in a compliant cast of a human aortic bifurcation. J. Biomech. Eng. 117, 219–223.
Chandran, K. B. (1993) Flow dynamics in the human aorta. J. Biomech. Eng. 115, 611–616.
Farthing, S. and Peronneau, P. (1979) Flow in the thoracic aorta. Cardiovasc. Res. 13, 607–620.
Hamakiotes, C. C. and Berger, S. A. (1988) Fully developed pulsatile flow in a curved pipe. J. Fluid Mech. 195, 23–55.
Hamakiotes, C. C. and Berger, S. A. (1990) Periodic flows through curved tubes: the effect of the frequency parameter. J. Fluid Mech. 210, 353–370.
Cheer, A. Y., Dwyer, H. A., Barakat A. I., Sy, E., and Bice, M. (1998) Computational study of the effect of geometric and flow parameters on the steady flow field at the rabbit aorto-celiac bifurcation. Biorheology 35, 415–435.
Sherwin, S. J., Shah, O., Doorly, D. J., Peiro, J. Papaharilaou, Y., Watkins, N., et al. (2000) The influence of out-of-plane geometry on the flow within a distal end-to-side anastomosis. J. Biomech. Eng. 122, 86–95.
Lei, M., Kleinstreuer, C., and Truskey, G. A. (1995) Numerical investigation and prediction of atherogenic sites in branching arteries. J. Biomech. Eng. 117, 350–357.
Reneman, R. S., van Merode, T., Hick, P., and Hoeks, A. P. G. (1985) Flow velocity patterns in and distensibility of the carotid artery bulb in subjects of various ages. Circulation 71, 500–509.
Liepsch, D. and Moravec, S., (1984) Pulsatile flow of non-Newtonian fluid in distensible models of human arteries. Biorheology 21, 571–586.
Kleinstreuer, C., Hyun, S., Buchanan, J. R., Jr., Longest, P. W., Archie, J. P. Jr., and Truskey, G. A. (2001) Hemodynamic parameters and early intimal thickening, in branching blood vessels. Crit. Rev. Biomed. Eng. 29, 1–64.
Barakat, A. I., Lever E. V., Pappone, P. A., and Davies, P. E. (1999) A flow-activated chloride selective membrane current in vascular endothelial cells. Circ. Res. 85, 820–828.
Jacobs, E. R., Cheliakine, C., and Davies, P. F. (1995) Shear activated channels in cell-attached patches of cultured bovine aortic endothelial cells. Pflug. Arch. 431, 129–131.
Nakache, M., and Gaub, H. E. (1988) Hydrodynamic hyperpolarization of endothelial cells. Proc. Natl. Acad. Sci. USA 85, 1841–1843.
Nakao, M., Ono, K., Fujisawa, F., and Iijima, T. (1999) Mechanical stress-induced Ca2+ entry and Cl− current in cultured human aortic endothelial cells. Am. J. Physiol. 276, C238-C249.
Olesen, S., Clapham, D. E., and Davies, P. F. (1988) Haemodynamic shear stress activates a K+ current in vascular endothelial cells. Nature 331, 168–170.
Gudi, S. R. P., Clark, C. B., and Frangos, J. A. (1996) Fluid flow rapidly activates G proteins in human endothelial cells—involvement of G proteins in mechanochemical signal transduction. Circ. Res. 79, 834–839.
Gudi, S., Nolan, J. P., and Frangos, J. A. (1998) Modulation of GTPase activity of G proteins by fluid shear stress and phospholipid composition. Proc. Natl. Acad. Sci. USA 95, 2515–2519.
Cooke, J. P., Rossitch, E., Jr., Andon, N. A., Loscalzo, J., and Dzau, V. J. (1991) Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator J. Clin. Invest. 88, 1663–1671.
Milner, P., Kirkpatric, K. A., Ralevic, V., Toothill, M., Pearson, J., and Burnstock, G. (1990) Endothelial cells cultured from human umbilical vein release ATP, substance P and acetylcholine in response to increased flow. Proc. R. Soc. Lond. Biol. 241, 245–248.
Noris, M., Morigi, M., Donadelli, R., Aiello, S., Foppolo, M., Todeschini, M., et al. (1995) Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions. Circ. Res. 76, 536–543.
Ando, J., Komatsuda, T., and Kamiya, A. (1988) Cytoplasmic calcium response to fluid shear stress in cultured vascular endothelial cells. In Vitro Cell Dev. Biol. 24, 871–877.
Dull, R. O., and Davies, P. F. (1991) Flow modulation of agonist (ATP)-response (Ca2+) coupling in vascular endothelial cells. Am. J. Physiol. 161, H149-H154.
Geiger, R. V., Berk, B. C., Alexander, R. W., and Nerem, R. M. (1992) Flow-induced calcium transients in single endothelial cells: spatial and temporal analysis. Am. J. Physiol. 262, C1411-C1417.
Shen, J., Luscinskas, F. W., Connolly, A., Dewey, Jr., C. F., and Gimbrone, M. A., Jr. (1992) Fluid shear stress modulates cytosolic free calcium in vascular endothelial cells. Am. J. Physiol. 262, C384-C390.
Butler, P. J., Norwich, G., Weinbaum, S., and Chien, S. (2001) Shear stress induces a time-and position-dependent increase in endothelial cell membrane fluidity. Am. J. Physiol. 280, C962-C969.
Haidekker, M. A., L'Heureux, N., and Frangos, J. A. (2000) Fluid shear stress increases membrane fluidity in endothelial cells, a study with DCVJ fluorescence. Am. J. Physiol. 278, H1401-H1406.
Ziegelstein, R. C., Cheng, L., and Capogrossi, C. (1992) Flow-dependent cytosolic acidification of vascular endothelial cells. Science 258, 656–659.
Ohno, M., Gibbons, G. H., Dzau, V. J., and Cooke, J. P. (1993) Shear stress elevates endothelial cGMP-role of a potassium channel and G protein coupling. Circulation 88, 193–197.
Frangos, J. A., Eskin, S. G., McIntire, L. V., and Ives, C. L. (1985) Flow effects on prostacyclin production by cultured human endothelial cells. Science 227, 1477–1479.
Grabowski, E. F., Jaffe, E. A., and Weksler, B. B. (1985) Prostacyclin production by cultured endothelial cell monolayers exposed to step increases in shear stress. J. Lab. Clin. Med. 105, 36–43.
Helmke, B. P., Goldman, R. D., and Davies, P. F. (2000) Rapid displacement of vimentin intermediate filaments in living endothelial cells exposed to flow. Circ. Res. 86, 745–752.
Tseng, H., Peterson, T. E., and Berk, B. C. (1995) Fluid shear stress stimulates mitogen-activated protein kinase in endothelial cells. Circ. Res. 77, 869–878.
Yan, C., Takahashi, M., Okuda, M., Lee, J., and Berk, B. C. (1999) Fluid shear stress stimulates big mitogen-activated protein kinase 1 (BMK1) activity in endothelial cells. J. Biol. Chem. 274, 143–150.
Lan, Q., Mercurius, K. O., and Davies, P. F. (1994) Stimulation of transcription factors NF_B and AP1 in endothelial cells subjected to shear stress. Biochem. Biophys. Res. Commun. 201, 950–956.
Hsieh, H., Li, N., and Frangos, J. A. (1993) Pulsatile and steady flow induces c-fos expression in human endothelial cells. J. Cell Physiol. 154, 143–151.
Ranjan, V., and Diamond, S. L. (1993) Fluid shear stress induces synthesis and nuclear localization of c-fos in cultured human endothelial cells. Biochem. Biophys. Res. Commun. 196, 79–84.
Braddock, M., Schwachtgen, J., Houston, P., Dickson, M. C., Lee, M. J., and Campbell, C. J. (1998) Fluid shear stress modulation of gene expression in endothelial cells. News Physiol. Sci. 13, 241–246.
Garcia-Cardena, G., Comander, J., Anderson, K. R., Blackman, B. R., and Gimbrone, M. A., Jr. (2001) Biomechanical activation of vascular endothelium as a determinant of its functional phenotype. Proc. Natl. Acad. Sci. USA 98, 4478–4485.
Malek, A. M., and Izumo, S. (1992) Physiological fluid shear stress causes downregulation of endothelin-1 mRNA bovine aortic endothelium. Am. J. Physiol. 263, C389-C396.
Yoshizumi, M., Kurihara, H., Sugiyama, T., Takaku, F., Yanagisawa, M., Masaki, T., and Yazaki, Y. (1989) Hemodynamic shear stress stimulates endothelin production by cultured endothelial cells. Biochem. Biophys. Res. Commun. 161, 859–864.
Malek, A. M., Izumo, S., and Alper, S. L. (1999) Modulation by pathophysiological stimuli of the shear stress-induced up-regulation of endothelial nitric oxide synthase expression in endothelial cells. Neurosurgery 45, 334–345.
Uematsu, M., Ohara, Y., Navas, J. P., Nishida, K., Murphy, T. J., Alexander, R. W., et al. (1995) Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress. Am. J. Physiol. 269, C1371-C1378.
Bao, X., Lu, C., and Frangos, J. A. (1999) Temporal gradients in shear but not steady shear stress induces PDGF-A and MCP-1 expression in endothelial cells—role of NO, NFκB, and egr-1. Arterioscler. Thromb. Vasc. Biol. 19, 996–1003.
Hsieh, H., Li, N., and Frangos, J. A. (1991) Shear stress increases endothelial platelet-derived growth factor mRNA levels. Am. J. Physiol. 29, H642-H646.
Malek, A. M., Gibbons, G. H., Dzau, V. J., and Izumo, S. (1993) Fluid shear stress differentially modulates expression of genes encoding basic fibroblast growth factor and platelet-derived growth factor B chain in vascular endothelium. J. Clin. Invest. 92, 2013–2021.
Lum, R. M., Wiley, L. M., and Barakat, A. I. (2000) Influence of different forms of fluid shear stress on vascular endothelial TGF-betal1 mRNA expression. Int. J. Mol. Med. 5, 635–641.
Ohno, M., Cooke, J. P., Dzau, V. J., and Gibbons, G. H. (1995) Fluid shear stress induces endothelial transforming growth factor beta-1 transcription and production. J. Clin. Invest. 95, 1363–1369.
Nagel, T., Resnick, N., Atkinson, W. J., Dewey, Jr., C. F., and Gimbrone, Jr., M. A. (1994) Shear stress selectively upregulates, intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells. J. Clin. Invest. 94, 885–891.
Tsuboi, H., Ando, J., Korenga, R., Takada, Y., and Kamiya, A. (1995) Flow stimulates ICAM-1 expression time and shear stress dependently in cultured human endothelial cells. Biochem. Biophys. Res. Commun. 206, 988–996.
Kudo, S., Morigaki, R., Saito, J., Ikeda, M., Oka, K., and Tanishita, K. (2000) Shear-stress effect on mitochondrial membrane potential and albumin uptake in cultured endothelial cells. Biochem. Biophys. Res. Commun. 270, 616–621.
Sprague, E. A., Steinbach, B. L., Nerem, R. M., and Schwartz, C. J. (1987) Influence of a luminar steady-state fluid-imposed wall shear stress on the binding, internalization, and degradation of low-density lipoprotein by cultured arterial endothelium. Circulation 76, 648–656.
Sato, M., Levesque, M. J., and Nerem, R. M. (1987) Micropipette aspiration of cultured bovine aortic endothelial cells exposed to shear stress. Arteriosclerosis 7, 276–286.
Sato, M., Ohshima, N., and Nerem, R. M. (1996) Viscoelastic properties of cultured porcine aortic endothelial cells exposed to shear stress. J. Biomech. 29, 461–467.
Nerem, R. M., Levesque, M. J., and Cornhill, J. F. (1981) Vascular endothelial morphology as an indicator of the pattern of blood flow. J. Biomech. Eng. 103, 172–177.
Ookawa, K., Sato, M., and Ohshima, N. (1992) Changes in the microstructure of cultured porcine aortic endothelial cells in the early stage after applying a fluid-imposed shear stress. J. Biomech. 25, 1321–1328.
Wechezak, A. R., Viggers, R. F., and Sauvage, L. R. (1985) Fibronectin and F-actin redistribution in cultured endothelial cells exposed to shear stress. Lab. Invest. 53, 639–647.
Wechezak, A. R., Wight, T. N., Viggers, R. F., and Sauvage, L. R. (1989) Endothelial adherence under shear stress is dependent upon microfilament reorganization. J. Cell Physiol. 139, 136–146.
Dewey, Jr., C. F., Bussolari, S. R., Gimbrone, Jr., M. A., and Davies, P. F. (1981) The dynamic response of vascular endothelial cells to fluid shear stress. J. Biomech. Eng. 103, 177–185.
Eskin, S. G., Ives, C. L., McIntire, L. V., and Navarro, L. T. (1984) Response of cultured endothelial cells to steady flow. Microvasc. Res. 28, 87–93.
Suvatne, J., Barakat, A. I., and O'Donnell, M. A. (2001) Flow-induced expression of endothelial Na−K−Cl cotransport: dependence on K+ and Cl− channels Am. J. Physiol. 180, C216-C227.
Nilius, B., and Droogmans, G. (2001) Ion channels and their functional role in vascular endothelium. Physiol. Rev. 81, 1415–1459.
Berthiaume, F., and Frangos, J. A. (1992) Flow-induced prostacyclin production is mediated by a pertussis toxin-sensitive G protein. FEBS Lett. 308, 277–279.
Barbee, K. A., Mundel, T., Lal, R., and Davies, P. F. (1995) Subcellular distribution of shear stress at the surface of flow aligned and non-aligned endothelial monolayers. Am. J. Physiol. 268, H1765-H1772.
Barakat, A. I., Marini, R. P., and Colton, C. K. (1997b) Measurement of flow rates through aortic branches in the anesthetized rabbits. Lab. Anim. Sci. 47, 184–189.
Davies, P. F., Remuzzi, A., Gordon, E. J., Dewey, C. F., Jr., and Gimbrone, E. A., Jr. (1986) Turbulent fluid shear stress induces vascular endothelial cell turnover in vitro. Proc. Natl. Acad. Sci. 83, 2114–2117.
Malek, A. M., Jackman, R., Rosenberg, R. D., and Izumo, S. (1994) Endothelial expression of thrombomodulin is reversibly regulated by fluid shear stress. Circ. Res. 74, 852–860.
Helminger, G., Berk, B. C., and Nerem, R. M. (1995) Calcium responses of endothelial cell monolayers subjected to pulsatile and steady laminar flow differ. Am. J. Physiol. 269, C367-C375.
Peng, X., Recchia, F. A., Byrne, B. J., Wittstein, I. S., Ziegelstein, R. C., and Kass, D. A. (2000) In vitro system to study realistic pulsatile flow and stretch signaling in cultured vascular cells. Am. J. Physiol. 279, C797-C805.
Lieu, D. K., Pappone, P. A., and Barakat, A. I. (2001) Role of ion channels in shear stress sensing in vascular endothelial cells. Ann. Biomed. Eng. 29, S-27.
Levesque, M. J., and Nerem, R. M. (1990) Vascular endothelial cell proliferation in cultured and the influence of flow. Biomaterials 11, 702–707.
Helminger, G., Geiger, R. V., Schreck, S., and Nerem, R. M. (1991) Effects of pulsatile flow on cultured vascular endothelial cell morphology. J. Biomech. Eng. 113, 123–131.
Ando, J., Ohtsuka, A., Korenaga, R., Kawamura, T., and Kamiya, A. (1993) Wall shear stress rather than shear rate regulates cytoplasmic Ca++ responses to flow in vascular endothelial cells. Biochem. Biophys. Res. Commun. 190, 716–723.
Nollert, M. U., and McIntire, L. V. (1992) Convective mass transfer effects on the intracellular calcium response of endothelial cells. J. Biomech. Eng. 114, 321–326.
Shen, J., Gimbrone, M. A., Jr., Luscinskas, F. W., and Dewey, C. F. Jr. (1993) Regulation of adenine nucleotide concentration at endothelium-fluid interface by viscous shear stress. Biophys. J. 64, 1323–1330.
John, K., and Barakat, A. I. (2001) Modulation of ATP/ADP concentration at the endothelial surface by shear stress: effect of flow-induced ATP release. Ann. Biomed. Eng. 29, 740–751.
Barakat, A. I. (2001) A model for shear, stress-induced deformation of a flow sensor on the surface of vascular endothelial cells. J. Theor. Biol. 210, 221–236.
Ziegler, T., Bouzourene, K., Harrison, V. J., Brunner, H. R., and Hayoz, D. (1998) Influence of oscillatory and unidirectional flow environments on the expression of endothelin and nitric oxide synthase in cultured endothelial cells. Arterioscler. Thromb. Vasc. Biol. 18, 686–692.
Manevich, Y., Al-Mehdi, A., Muzykantov, V., and Fisher, A. B. (2001) Oxidative burst and NO generation as initial response to ischemia in flow-adapted endothelial cells. Am. J. Physiol. 280, H2126-H2135.
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Barakat, A.I., Lieu, D.K. Differential responsiveness of vascular endothelial cells to different types of fluid mechanical shear stress. Cell Biochem Biophys 38, 323–343 (2003). https://doi.org/10.1385/CBB:38:3:323
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DOI: https://doi.org/10.1385/CBB:38:3:323