Skip to main content
SpringerLink
Log in

Flow-Mediated Signal Transduction in Endothelial Cells

  • Chapter
Flow-Dependent Regulation of Vascular Function

Part of the book series: Clinical Physiology Series ((CLINPHY))

Abstract

In vivo, endothelial cells are exposed to a complex mechanical and chemical environment that influences their structure and function. As the cellular interface between the flowing blood and the arterial wall, the endothelium effectively represents the outer boundary of the vascular tissue, and as such, it performs the important function of transmitting and transducing information from the blood to the rest of the vessel wall (8). This is particularly important in terms of the physiological regulation of lumen diameter, the maintenance of anticoagulant properties at the endothelial surface, the regulation of vascular permeability, and the pathological consequences associated with acute inflammation, wound healing, and cardiovascular disorders, such as the focal localization of atherosclerosis. In all of the above processes, the endothelium is involved in a stimulus-response coupling with humoral and/or mechanical factors in the blood. The nature of endothelial signal transduction ranges from extremely rapid electrophysiological (ion channels) responses to relatively slow gene regulatory and structural/morphologic changes. Many of these responses are only generated by the direct action of mechanical flow forces upon the endothelial cell; others, however, are only indirectly related to hemodynamic factors when flow alters the local concentration gradients of chemical mediators at the endothelial cell surface, and the mediators in turn regulate the cellular responses. The direct mechanisms primarily involve mechanical stretching that results from (1) pressure changes and (2) frictional forces at the endothelial surface in the direction of flow (shear stress). In contrast, the concentration gradient of chemical mediators at the cell surface is altered by mass transport (convection/diffusion) acting in concert with degradative enzymes at the endothelial cell surface. In this chapter, the responses of endothelial cells to flow and mechanical perturbation are summarized, ion channels are considered as a potential mechanosensor system, and examples of direct and indirect (chemical) transduction are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ando, J., T. Komatsuda, and A. Kamiya. Cytoplasmic calcium responses to fluid shear stress in cultured vascular endothelial cells. In Vitro Cell Deu. Biol. 24: 871–877, 1988.

    Article  CAS  Google Scholar 

  2. la. Barbee, K. A., P. F. Davies, and R. Lal. Shear stress-induced reorganization of the surface topography of living endothelial cells imaged by atomic force microscopy. Circ. Res. 74: 163–171, 1994.

    Article  PubMed  CAS  Google Scholar 

  3. Bodin, P., D. Bailey, and G. Burnstock. Increased flow-Atp release from isolated vascular endothelial cells but not smooth muscle cells Brit. J. Pharmacol. 103: 1203–1205, 1991.

    Article  CAS  Google Scholar 

  4. Braam, J., and R. W. Davis. Rain, wind and touch-induced expression of calmodulin and calmodulin-related genes in Arabidopsis. Cell 60: 357–364, 1990.

    Article  PubMed  CAS  Google Scholar 

  5. Burridge, K., K. Fath, T. Kelly, G. Nuckells, and C. Turner. Focal adhesions: trans-membrane junctions between the extracellular matrix and the cytoskeleton Annu. Rev. Cell Biol. 4: 487–525, 1988.

    Article  CAS  Google Scholar 

  6. Burton, F. L., and O. F. Hutter. Sensitivity to flow of intrinsic gating in inwardly rectifying potassium channel from mammalian skeletal muscle. J. Physiol. (Lond) 424: 253261, 1990.

    Google Scholar 

  7. Cooke, J. P., E. Rossitch, N. A. Andon, J. Loscalzo, and V. Dzau. Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J. Clin Invest. 88: 1663–1671, 1991.

    Article  PubMed  CAS  Google Scholar 

  8. Davies, P. F. Endothelial cells, hemodynamic forces and the localization of atherosclerosis. In Endothelial Cells,Vol II, ed. U. S. Ryan. Boca Raton: Crc Press, 1988, pp. 123139.

    Google Scholar 

  9. Davies, P. F. How do vascular endothelial cells respond to flow? News Physiol. Sci. 4: 2226, 1989.

    Google Scholar 

  10. Davies, P. F., C. F. Dewey, S. R. Bussolari, E. J. Gordon, and M. A. Gimbrone. Influence of hemodynamic forces on vascular endothelial function J. Clin. Invest. 73: 1121–1129, 1983.

    Article  Google Scholar 

  11. Davies, P. F., A. Remuzzi, E. S. Gordon, C. F. Dewey, and M. A. Gimbrone. Turbulent shear stress induces vascular endothelial turnover in vitro. Proc. Nat. Acad. Sci. Usa 83: 2114–2118, 1986.

    Article  PubMed  CAS  Google Scholar 

  12. Davies, P. F., A. Robotewskyj, and M. L. Griem. Quantitative studies of endothelial cell adhesion: Directional remodeling of focal adhesion sites in response to flow forces. J. Clin. Invest. 93: 2031–2038, 1994.

    Article  PubMed  CAS  Google Scholar 

  13. DE Paola, N., C. F. Dewey, P. F. Davies, and M. A. Gimbrone. Vascular endothelium responds to fluid shear stress gradients. Arterioscl. Thromb. 12: 1254–1259, 1992.

    Article  Google Scholar 

  14. Dewey, C. F., S. R. Bussolari, M. A. Gimbrone, and P. F. Davies. The dynamic response of vascular endothelial cells to fluid shear stress J. Biomech. Eng. 103: 177–188, 1981.

    Article  PubMed  Google Scholar 

  15. Diamond, S. L., S. G. Eskin, and L. V. Mcintire. Fluid flow stimulates tissue plasminogen activator secretion by cultured human endothelial cells. Science 243: 1483–1485, 1989.

    Article  PubMed  CAS  Google Scholar 

  16. Diamond, S. L., J. B. Sharefkin, C. Dieffenbach, K. Frazier-Scott, L. V. Mcintire, and S. G. Eskin. Tissue plasminogen activator mRna levels increase in cultured human endothelial cells exposed to laminar shear stress J. Cell. Physiol. 143: 364–371, 1990.

    Article  PubMed  CAS  Google Scholar 

  17. Diamond, S. L., J. B. Sharefkin, C. W. Dieffenbach, S. G. Eskin, and L. V. Mcintire. Regulation of endothelial cell gene expression by hemodynamic forces: implications for intimal hyperplasia and graft patency. In Technologies in Vascular Surgery, Ed. J. Yao and W. H. Pearce, eds. Philadelphia: W. B. Saunders, 1992, pp 12–24.

    Google Scholar 

  18. Dull, R. O., and P. F. Davies. Flow modulation of agonist (Atp)-response (Ca` ~) coupling in vascular endothelial cells Am J. Physiol. 261 (Heart Circ. Physiol. 30 ): H149 - H156, 1991.

    Google Scholar 

  19. Dull, R. O., J. M. Tarbell, and P. F. Davies. Mechanisms of flow-mediated signal transduction in endothelial cells: kinetics of Atp surface concentrations. J. Vasc. Res. 1992, 29: 410–419.

    Article  PubMed  CAS  Google Scholar 

  20. Eskin, S. G., C. L. Ives, L. V. Mcintire, and L. T. Navarro. Response of cultured endothelial cells to steady flow. Microvasc. Res. 28: 87–93, 1984.

    Article  PubMed  CAS  Google Scholar 

  21. Frangos, J. A., S. G. Eskin, L. V. Mcintire, and C. L. Ives. Flow effects on prostacyclin production by cultured human endothelial cells Science 227: 1477–1479, 1985.

    CAS  Google Scholar 

  22. Frangos, J. A., and M. J. Kuchan. Fluid flow activates G-proteins that are coupled to Ca-dependent and -independent Edrf production in cultured endothelial cells. Faseb J. 5: A1820 (Abstract), 1991.

    Google Scholar 

  23. Franke, R. P., M. Grafe, H. Schnittler, D. Seiffge, C. Mittermayer, and D. Drenckhahn. Induction of human vascular endothelial stress fibers by fluid shear stress. Nature 307: 648, 1984.

    Article  PubMed  CAS  Google Scholar 

  24. Geiger, R. V., B. C. Berk, R. W. Alexander, and R. M. Nerem. Flow-induced calcium transients in single endothelial cells: spatial and temporal analysis Am. J. Physiol. 262 (Cell Physiol 31 ): C1411 - C1417, 1992.

    Google Scholar 

  25. Girard P. R., and R. M. Nerem. Role of protein kinase C in the transduction of shear stress to alterations of endothelial cell morphology J. Cell Biochem. 14E: 210 (Abstract), 1990.

    Google Scholar 

  26. Goligorsky, M. S. Mechanical stimulation induces Ca’, transients and membrane depolarization in cultured endothelial cells. Effects on Cam +; in co-perfused smooth muscle cells. Febs Lett. 240: 59–64, 1988.

    Google Scholar 

  27. GrabowsKI, E. F., B. B. Weksler, and E. A. Jaffe. Prostacyclin production by cultured endothelial cell monolayers exposed to step increases in shear stress J. Lab. Clin. Med. 105: 36–43, 1985.

    Google Scholar 

  28. Guharay, F., and F. Sachs. Stretch-activated single ion channel currents in tissue cultured embryonic chick skeletal muscle cells J. Physiol. (Lond) 352: 685–701, 1984.

    CAS  Google Scholar 

  29. Gupte, A., and J. A. Frangos. Effects of flow on the synthesis and release of fibronectin by endothelial cells. In Vitro Cell Dev. Biol. 26: 57–60, 1990.

    Article  PubMed  CAS  Google Scholar 

  30. Ho, K., C. G., Nichols, W. J. Lederer, J. Lytton, P. M. Vasiliev, M. V. Kanazirska, and S. C. Hebert. Cloning and expression of an inwardly rectifying Atp-regulated K channel. Nature 362: 31–38, 1993.

    CAS  Google Scholar 

  31. Honda, H. M., C. Wortham, M. Navab, and L. L. Demer. Disturbed flow induces heat shock protein-70 mRna in bovine and human aortic endothelial cells. Circulation (Suppl. I) 86: I-224, (Abstract), 1992.

    Google Scholar 

  32. Hsieh, H. J., N. Q. LI, and J. A. Frangos. Pulsatile and steady flows increase protooncogenes c-fos and c-myc mRna levels in human endothelial cells. Faseb J. 5: A 1820 (Abstract), 1991.

    Google Scholar 

  33. Hsieh, H. J., N. Q. Li, and J. A. Frangos. Shear-induced platelet derived growth factor gene expression in human endothelial cells is mediated by protein kinase C. J. Cell Physiol. 150: 552–558, 1992.

    Article  PubMed  CAS  Google Scholar 

  34. Iba, T., and B. E. Sumpio. Morphological response of human endothelial cells subjected to cyclic strain in vitro. Microvasc. Res. 42: 245–254, 1991.

    Article  PubMed  CAS  Google Scholar 

  35. Ingber, D. Integrins as mechanochemical transducers Curr. Opin. Cell Biol. 3: 841–848, 1991.

    Article  PubMed  CAS  Google Scholar 

  36. Karino, T., and M. Motomiya. Flow visualization in isolated transparent natural blood vessels. Biorheology 20: 119–127, 1983.

    PubMed  CAS  Google Scholar 

  37. Komuro, I., Y. Katoh, T. Kaida, Y. Shibazaki, M. Kurabayashi, E. Hoh, F. Takaku, and Y. Yazaki. Mechanical loading stimulates cell hypertrophy and specific gene expression in cultured rat cardiac myocytes: possible role of protein kinase C activation. J. Biol. Chem. 266: 1265–1268, 1991.

    PubMed  CAS  Google Scholar 

  38. Kubo, Y., E. Renvey, P. A. Slesinger, Y. N. Jan, and L. Y. Jan. Primary structure and functional expression of a rat G-protein-coupled muscarinic K channel. Nature 364: 30 2806, 1993.

    Google Scholar 

  39. Lansman, J. B., T. J. Hallam, and T. J. Rink. Single stretch-activated ion channels in vascular endothelial cells as mechanotransducers? Nature 325: 811–812, 1987.

    Article  PubMed  CAS  Google Scholar 

  40. Letsou, G. V., O. Rosales, S. Maitz, A. Vogt, and B. E. Sumpio. Stimulation of adenylate cyclase activity in cultured endothelial cells subjected to cyclic stretch J. Cardiouasc. Surg. 31: 634–639, 1990.

    CAS  Google Scholar 

  41. Malek, A., and S. Izublo. Physiological fluid shear stress causes down-regulation of endothelin-1 mRna in bovine aortic endothelium. Am. J. Physiol. 263 (Cell Physiol 32 ): C389 - C396, 1992.

    Google Scholar 

  42. Milner, P., K. A. Kirkpatrick, V. Ralevic, V. Toothill, J. D. Pearson, and G. Burnstock. Endothelial cells cultured from umbilical vein release Atp, substance P and acetylcholine in response to increased flow. Proc. Roy. Soc. B 241: 245–248, 1990.

    Article  CAS  Google Scholar 

  43. Mo, M., S. G. Eskin, and W. P. Schilling. Flow-induced changes in Ca’ signaling of vascular endothelial cells: effect of shear stress and Atp. Am. J. Physiol. 260 (Heart Circ. Physiol. 29 ): H1698 - H1707, 1991.

    Google Scholar 

  44. Morris, C. E. and R. Horn. Failure to elicit neuronal macroscopic mechanosensitive currents anticipated by single-channel studies. Science 251: 1246–1249, 1991.

    Article  PubMed  CAS  Google Scholar 

  45. Morris, C. E., and W. S. Sigurdson. Stretch-inactivated ion channels coexist with stretch-activated ion channels. Science 243: 807–809, 1989.

    Article  PubMed  CAS  Google Scholar 

  46. Nakache, M., and H. E. Gaub. Hydrodynamic hyperpolarization of endothelial cells. Proc. Nat. Acad. Usa 85: 1841–1843, 1988.

    Article  CAS  Google Scholar 

  47. Nollert, M. U., S. L. Diamond, and L. V. Mcintire. Hydrodynamic shear stress and mass transport modulation of endothelial cell metabolism. Biotech. Bioeng. 38: 588–595, 1991.

    Article  CAS  Google Scholar 

  48. Nollert, M. U., S. G. Eskin, and L. V. Mcintire. Shear stress increases inositol trisphosphate levels in human endothelial cells. Biochem. Biophys. Res. Comm. 170: 281, 1990.

    Article  PubMed  CAS  Google Scholar 

  49. Ohno, M., G. H. Gibbons, V. Dzau, and J. P. Cooke. Shear stress elevates endothelial cGmp: Role of potassium channel and G-protein coupling. Circulation 88: 193–197, 1993.

    CAS  Google Scholar 

  50. Olesen, S-P., P. F. Davies, and D. E. Clapham. Muscarinic acetylcholine-activated K current in bovine aortic endothelial cells. Circ. Res. 62: 1058–1064, 1988.

    Article  Google Scholar 

  51. Olesen, S. P., D. E. Clapham, and P. F. Davies. Hemodynamic shear stress activates a K’ current in vascular endothelial cells. Nature 331: 168–170, 1988.

    Article  PubMed  CAS  Google Scholar 

  52. Resnick N., T. Collins, W. Atkinson, D. T. Bonthron, C. F. Dewey, and M. A. Gimbrone. Platelet-derived growth factor B chain promoter contains a cis-acting fluid shear stress-responsive element. Proc. Natl. Acad. Sci. Usa 90: 4591–4595, 1993.

    Article  PubMed  CAS  Google Scholar 

  53. Robotewskyj, A., R. O. Dull, M. L. Griem, and P. F. Davies. Dynamics of focal adhesion site remodelling in living endothelial cells in response to shear stress forces using confocal image analysis. Faseb J. 5: A527 (Abstract), 1991.

    Google Scholar 

  54. Rosales, O. R., and B. E. Sumpio. Changes in cyclic strain increase inositol trisphosphate and diacylglycerol in endothelial cells. Am. J. Physiol. 262 (Cell Physiol 31 ): C956 - C962, 1992.

    Google Scholar 

  55. Sato, M., M. J. Levesque, and R. M. Nerem. Micropipette aspiration of cultured bovine aortic endothelial cells exposed to shear stress. Arteriosclerosis 7: 276–286, 1987.

    Article  PubMed  CAS  Google Scholar 

  56. Schultz, J. E., S. Klumpp, R. Benz, W. J. Schurhoff-Goeters, and A. Schmid. Regulation of adenylyl cyclase from Paramecium by an intrinsic potassium conductance. Science 255: 600–603, 1992.

    CAS  Google Scholar 

  57. Sharefkin, J. B., S. L. Diamond, S. G. Eskin, L. V. Mcintire, and C. W. Dieffenbach. Fluid flow decreases preproendothelin mRna levels and suppresses endothelin-1 peptide release in cultured human endothelial cells. J. Vasc. Surg. 14: 1–9, 1991.

    Article  PubMed  CAS  Google Scholar 

  58. Shen, J., F. W. Luscinskas, A. Connolly, C. F. Dewey, and M. A. Gimbrone. Fluid shear stress modulates cytosolic free calcium in vascular endothelial cells. Am. J. Physiol. 262 (Cell Physiol 31 ): C384, 1992.

    Google Scholar 

  59. Shirinsky, V. P., A. S. Antonov, K. G. Birukov, A. V. Sobolevsky, Y. A. Romanov, N. V. Kabaeva, G. N. Antonova, and V. N. Smirnov. Mechano-chemical control of human endothelium orientation and size. J. Cell Biol. 109: 331–339, 1989.

    Article  PubMed  CAS  Google Scholar 

  60. Skarlatos, S. I., and T. M. Hollis. Cultured bovine aortic endothelial cells show increased histamine metabolism when exposed to oscillatory shear stress. Atherosclerosis 64: 55–61, 1987.

    Article  PubMed  CAS  Google Scholar 

  61. Sprague, E. A., B. L. Steinbach, R. M. Nerem, and C. J. Schwartz. Influence of a laminar steady state fluid imposed wall shear stress on the binding, internalization and degradation of Ldl by cultured arterial endothelium. Circulation 76: 648–656, 1987.

    Article  PubMed  CAS  Google Scholar 

  62. Sumpio, B. E., A. J. Banes, M. Buckley, and G. Johnson. Alterations in aortic endothelial cell morphology and cytoskeletal protein synthesis during cyclic tensional deformation. J. Vasc. Surg. 7: 130–138, 1987.

    Google Scholar 

  63. Sumpio, B. E., A. J. Banes, G. W. Link, and T. Iba. Modulation of endothelial phenotype by cyclic stretch: inhibition of collagen production. J. Surg. Res. 48: 415–420, 1990.

    Article  PubMed  CAS  Google Scholar 

  64. Taylor, W. R., D. G. Hanson, R. M. Nerem, T. E. Peterson, and R. W. Alexander. Characterization of the release of endothelial-derived nitrogen oxides by shear stress. Faseb J. 5: A1727 (Abstract), 1991.

    Google Scholar 

  65. Watson, P.A. Direct stimulation of adenylate cyclase by mechanical forces in S49 mouse lymphoma cells during hyposmotic swelling. J. Biol. Chem. 265: 6569–6575, 1990.

    PubMed  CAS  Google Scholar 

  66. Wechezak, A. R., R. F. Viggers, and L. R. Sauvage. Fibronectin and F-actin redistribution in cultured endothelial cells exposed to shear stress. Lab. Invest. 53: 639–647, 1985.

    PubMed  CAS  Google Scholar 

  67. Wechezak, A. R., T. N. Wight, R. F. Viggers, and L. R. Sauvage. Endothelial adherence under shear stress is dependent upon microfilament reorganization. J. Cell. Physiol. 139: 136–146, 1989.

    Article  PubMed  CAS  Google Scholar 

  68. Yoshizumi, M., H. Kurihara, T. Sugiyama, F. Takaku, M. Yanagisawa, T. Masaki, and Y. Yazaki. Hemodynamic shear stress stimulates endothelin production by cultured endothelial cells. Biochem. Biophys. Res. Comm. 161: 859–864, 1989.

    Article  PubMed  CAS  Google Scholar 

  69. Ziegelstein, R. C., L. Cheng, and M. C. Capogrossi. Flow dependent cytosolic acidification of vascular endothelial cells. Science 258: 656–659, 1992.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Peter F. Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Pharmacology, College of Medicine, University of Vermont, Burlington, Vermont, USA

    John A. Bevan M.D.

  2. Department of Physiology, New York Medical College, Valhalla, New York, USA

    Gabor Kaley Ph.D.

  3. Berlex Biosciences, Richmond, California, USA

    Gabor M. Rubanyi M.D., Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 1995 American Physiological Society

About this chapter

Cite this chapter

Davies, P.F. (1995). Flow-Mediated Signal Transduction in Endothelial Cells. In: Bevan, J.A., Kaley, G., Rubanyi, G.M. (eds) Flow-Dependent Regulation of Vascular Function. Clinical Physiology Series. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7527-9_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-7527-9_3

  • Publisher Name: Springer, New York, NY

  • Online ISBN: 978-1-4614-7527-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation