Abstract
Vascular endothelial cells (ECs) play significant roles in regulating circulatory functions. The shear stress resulting from blood flow modulates EC functions by activating mechano-sensors, signaling pathways, and gene and protein expressions. Shear stress with a clear direction resulting form pulsatile or steady flow causes only transient activation of pro-inflammatory and proliferative pathways, which become down-regulated when such directed shearing is sustained. In contrast, shear flow without a definitive direction (e.g., disturbed flow in regions of complex geometry) causes sustained molecular signaling of pro-inflammatory and proliferative pathways. The EC responses to shear flows with a clear direction involve the remodeling of EC structure to maintain vascular homeostasis and are athero-protective. Such regulatory mechanism does not operate effectively when the flow pattern is disturbed. Therefore, the branch points and other regions of the arterial tree with a complex geometry are prone to atherogenesis, whereas the straight part of the arterial tree is generally spared. Understanding of the EC responses to different flow patters helps to elucidate the mechanism of the region-specific localization of atherosclerosis in the arterial system.
Similar content being viewed by others
References
Chen Y. L., K. M. Jan, H. S. Lin, S. Chien. Ultrastructural studies on macromolecular permeability in relation to endothelial cell turnover. Atherosclerosis 118:89–104, 1995
Chien S. Molecular and mechanical bases of focal lipid accumulation in arterial wall. Prog. Biophys. Mol. Biol. 83:131–151, 2003
Chien S. Molecular basis of rheological modulation of endothelial functions: importance of stress direction. Biorheology 43:95–116, 2006
Chien S. Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell. Am. J. Physiol. Heart Circ. Physiol. 292:H1209–H1224, 2007
Chien S., S. J. Lin, S. Weinbaum, M. M. Lee, K. M. Jan. The role of arterial endothelial cell mitosis in macromolecular permeability. Adv. Exp. Med. Biol. 242:59–73, 1988
Chiu J. J., D. L. Wang, S. Chien, R. Skalak, S. Usami. Effects of disturbed flow on endothelial cells. J. Biomech. Eng. 120:2–8, 1998
Chuang P. T., H. J. Cheng, S. J. Lin, K. M. Jan, M. M. Lee, S. Chien. Macromolecular transport across arterial and venous endothelium in rats. Studies with Evans blue-albumin and horseradish peroxidase. Arteriosclerosis 10:188–197, 1990
Colangelo S., B. L. Langille, A. I. Gotlieb. Three patterns of distribution characterize the organization of endothelial microfilaments at aortic flow dividers. Cell Tissue Res. 278: 235–242, 1994
Dai G., M. R. Kaazempur-Mofrad, S. Natarajan, Y. Zhang, S. Vaughn, et al. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature. Proc. Natl. Acad. Sci. USA 101:14871–14876, 2004
Fukushima T., T. Karino, H. L. Goldsmith. Disturbances of flow through transparent dog aortic arch. Heart Vessels 1:24–28, 1985
Galbraith C. G., R. Skalak, S. Chien. Shear stress induces spatial reorganization of the endothelial cell cytoskeleton. Cell Motil. Cytoskel. 40:317–330, 1998
Glagov S., C. Zarins, D. P. Giddens, D. N. Ku. Hemodynamics and atherosclerosis. Insights and perspectives gained from studies of human arteries. Arch. Pathol. Lab. Med. 112:1018–1031, 1988
Goldsmith H. L., T. Karino. Interactions of human blood cells with the vascular endothelium. Ann. N. Y. Acad. Sci. 516:468–483, 1987
Hsiai T. K., S. K. Cho, P. K. Wong, M. Ing, A. Salazar, et al. Monocyte recruitment to endothelial cells in response to oscillatory shear stress. FASEB J. 17:1648–1657, 2003
Huang A. L., K. M. Jan, S. Chien. Role of intercellular junctions in the passage of horseradish peroxidase across aortic endothelium. Lab. Invest. 67:201–209, 1992
Karino T., H. L. Goldsmith. Disturbed flow in models of branching vessels. Trans. Am. Soc. Art. Int. Org. 26:500–506, 1980
Karino T., H. L. Goldsmith, M. Motomiya, S. Mabuchi, Y. Sohara. Flow patterns in vessels of simple and complex geometries. Ann. N. Y. Acad. Sci. 516:422–441, 1987
Kuo C. T., M. L. Veselits, J. M. Leiden. Lklf and fasl expression: corrections and clarification. Science 278:788–789, 1997
Kwak B. R., F. Mulhaupt, N. Veillard, D. B. Gros, F. Mach. Altered pattern of vascular connexin expression in atherosclerotic plaques. Arterioscler. Thromb. Vasc. Biol. 22:225–230, 2002
Li Y. S., J. H. Haga, S. Chien. Molecular basis of the effects of shear stress on vascular endothelial cells. J. Biomech. 38:1949–1971, 2005
Li Y. S., J. Y. Shyy, S. Li, J. Lee, B. Su, et al. The Ras-JNK pathway is involved in shear-induced gene expression. Mol. Cell. Biol. 16:5947–5954, 1996
Lin K., P. P. Hsu, B. P. Chen, S. Yuan, S. Usami, et al. Molecular mechanism of endothelial growth arrest by laminar shear stress. Proc. Natl. Acad. Sci. USA 97:9385–9389, 2000
Lin S. J., K. M. Jan, S. Chien. Temporal and spatial changes in macromolecular uptake in rat thoracic aorta and relation to [3h]thymidine uptake. Atherosclerosis 85:229–238, 1990
Liu Y., B. P. Chen, M. Lu, Y. Zhu, M. B. Stemerman, et al. Shear stress activation of SREBP1 in endothelial cells is mediated by integrins. Arterioscler. Thromb. Vasc. Biol. 22:76–81, 2002
Malinauskas R. A., R. A. Herrmann, G. A. Truskey. The distribution of intimal white blood cells in the normal rabbit aorta. Atherosclerosis 115:147–163, 1995
Masuda H., T. Shozawa, S. Hosoda, M. Kanda, A. Kamiya. Cytoplasmic microfilaments in endothelial cells of flow loaded canine carotid arteries. Heart Vessels 1:65–69, 1985
Miao H., Y. L. Hu, Y. T. Shiu, S. Yuan, Y. Zhao, et al. Effects of flow patterns on the localization and expression of VE-cadherin at vascular endothelial cell junctions: in vivo and in vitro investigations. J. Vasc. Res. 42:77–89, 2005
Nerem R. M. Hemodynamics and the vascular endothelium. J. Biomech. Eng. 115:510–514, 1993
Schwenke D. C., T. E. Carew. Quantification in vivo of increased LDL content and rate of LDL degradation in normal rabbit aorta occurring at sites susceptible to early atherosclerotic lesions. Circ. Res. 62:699–710, 1988
Shyy J. Y., M. C. Lin, J. Han, Y. Lu, M. Petrime, S. Chien. The cis-acting phorbol ester “12-o-tetradecanoylphorbol 13-acetate”-responsive element is involved in shear stress-induced monocyte chemotactic protein 1 gene expression. Proc. Natl. Acad. Sci. USA 92: 8069–8073, 1995
Texon M. Hemodynamic Basis of Atherosclerosis: With Critique of the Cholesterol-heart Disease Hypothesis 2nd ed. New York: Begell House, 1995
Thoumine O., R. M. Nerem, P. R. Girard. Oscillatory shear stress and hydrostatic pressure modulate cell-matrix attachment proteins in cultured endothelial cells. In Vitro Cell Dev. Biol. Anim. 31:45–54, 1995
Truskey G. A., W. L. Roberts, R. A. Herrmann, R. A. Malinauskas. Measurement of endothelial permeability to 125i-low density lipoproteins in rabbit arteries by use of en face preparations. Circ. Res. 71:883–897, 1992
Tzima E., M. Irani-Tehrani, W. B. Kiosses, E. Dejana, D. A. Schultz, et al. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437:426–431, 2005
Walpola P. L., A. I. Gotlieb, B. L. Langille. Monocyte adhesion and changes in endothelial cell number, morphology, and f-actin distribution elicited by low shear stress in vivo. Am. J. Pathol. 142:1392–1400, 1993
Wang N., H. Miao, Y. S. Li, P. Zhang, J. H. Haga, et al. Shear stress regulation of Krüppel-like factor 2 expression is flow pattern-specific. Biochem. Biophys. Res. Commun. 341:1244–1251, 2006
Weinbaum S., G. Tzeghai, P. Ganatos, R. Pfeffer, S. Chien. Effect of cell turnover and leaky junctions on arterial macromolecular transport. Am. J. Physiol. 248:H945–H960, 1985
White G. E., M. A. Gimbrone Jr., K. Fujiwara. Factors influencing the expression of stress fibers in vascular endothelial cells in situ. J. Cell Biol. 97:416–424, 1983
Wong A. J., T. D. Pollard, I. M. Herman. Actin filament stress fibers in vascular endothelial cells in vivo. Science 219:867–869, 1983
Zhao Y., B. P. Chen, H. Miao, S. Yuan, Y. S. Li, et al. Improved significance test for DNA microarray data: temporal effects of shear stress on endothelial genes. Physiol. Genomics 12:1–11, 2002
Acknowledgments
This work was supported in part by grants HL43026, HL80518, and HL85159 from the National Heart, Lung, and Blood Institute. The author would like to acknowledge the valuable discussions with Dr. Harry Goldsmith and his inspirations on many of the experiments on blood cell rheology and flow dynamics.
Author information
Authors and Affiliations
Corresponding author
Additional information
An erratum to this article can be found at http://dx.doi.org/10.1007/s10439-010-9931-7
Rights and permissions
About this article
Cite this article
Chien, S. Effects of Disturbed Flow on Endothelial Cells. Ann Biomed Eng 36, 554–562 (2008). https://doi.org/10.1007/s10439-007-9426-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10439-007-9426-3