Cell Biochemistry and Biophysics

, Volume 46, Issue 3, pp 277–284 | Cite as

Flow-activated ion channels in vascular endothelium

  • Mamta Gautam
  • Andrea Gojova
  • Abdul I. Barakat


The ability of vascular endothelial, cells (ECs) to respond to fluid mechanical forces associated with blood flow is essential for flow-mediated vasoregulation and arterial wall remodeling. Abnormalities in endothelial responses to flow also play a role in the development of atherosclerosis. Although our understanding of the endothelial signaling pathways stimulated by flow has greatly increased over the past two decades, the mechanisms by which ECs sense flow remain largely unknown. Activation of flow-sensitive ion channels is among the fastest known endothelial responses to flow; therefore, these ion channels have been proposed as candidate flow sensors. This review focuses on: 1) describing the various types of flow-sensitive ion channels that have been reported in ECs, 2) discussing the implications of activation of these ion channels for endothelial function, and 3) proposing candidate mechanisms for activation of flow-sensitive ion channels.

Index Entries

Ion channels Endothelial cells Shear stress Atherosclerosis Flow Mechanotransduction 


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  1. 1.
    Langille, B. L. and O'Donnell, F. (1986) Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science 231, 405–407.PubMedCrossRefGoogle Scholar
  2. 2.
    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, 37–44.PubMedGoogle Scholar
  3. 3.
    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 oscillating shear stress. Arteriosclerosis 5, 293–302.PubMedGoogle Scholar
  4. 4.
    Nerem, R. M. (1992) Vascular fluid mechanics, the arterial wall, and atherosclerosis. J. Biomech. Eng. 114, 274–282.PubMedGoogle Scholar
  5. 5.
    Barakat, A. and Lieu, D. (2003) Differential responsiveness of vascular endothelial cells to different types of fluid mechanical shear stress. Cell Biochem. Biophys. 38, 323–343.PubMedCrossRefGoogle Scholar
  6. 6.
    Cunningham, K. S. and Gotlieb, A. I. (2005) The role of shear stress in the pathogenesis of atherosclerosis. Lab. Invest. 85, 9–23.PubMedCrossRefGoogle Scholar
  7. 7.
    Dai, G., Kaazempur-Mofrad, M. R., Natarajan, S., Zhang, Y., Vaughn, S., Blackman, B. R., Kamm, R. D., Garcia-Cardena, G., and Gimbrone, M. A., Jr. (2004) Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and resistant regions of human vasculature. Proc. Natl. Acad. Sci. U. S. A. 101, 14871–14876.PubMedCrossRefGoogle Scholar
  8. 8.
    Passerini, A. G., Polacek, D. C., Shi, C., Francesco, N. M., Manduchi, E., Grant, G. R., Pritchard, W. F., Powell, S., Chang, G. Y., Stoeckert, C. J., Jr., and Davies, P. F. (2004) Coexisting proinflammatory and antioxidative endothelial transcription profiles in a disturbed flow region of the adult porcine aorta. Proc. Natl. Acad. Sci. U. S. A. 101, 2482–2487.PubMedCrossRefGoogle Scholar
  9. 9.
    Tedgui, A. and Mallat, Z. (2001) Anti-inflammatory mechanisms in the vascular wall. Circ. Res. 88, 877–887.PubMedCrossRefGoogle Scholar
  10. 10.
    Chen, C. S., Tan, J., and Tien, J. (2004) Mechanotransduction at cell-matrix and cell-cell contacts. Annu. Rev. Biomed. Eng. 6, 275–302.PubMedCrossRefGoogle Scholar
  11. 11.
    Davies, P. F. (1995) Flow-mediated endothelial mechanotransduction. Physiol. Rev. 75, 519–560.PubMedGoogle Scholar
  12. 12.
    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. U. S. A. 98, 4478–4485.PubMedCrossRefGoogle Scholar
  13. 13.
    Huang, H., Kamm, R. D., and Lee, R. T. (2004) Cell mechanics and mechanotransduction: pathways, probes, and physiology. Am. J. Physiol. Cell Physiol. 287, C1-C11.PubMedCrossRefGoogle Scholar
  14. 14.
    Janmey, P. A. and Weitz, D. A. (2004) Dealing with mechanics: mechanisms of force transduction in cells. Trends Biochem. Sci. 29, 364–370.PubMedCrossRefGoogle Scholar
  15. 15.
    Lehoux, S., Castier, Y., and Tedgui, A. (2006) Molecular mechanisms of the vascular responses to haemodynamic forces. J. Intern. Med. 259, 381–392.PubMedCrossRefGoogle Scholar
  16. 16.
    Li, Y. S., Haga, J. H., and Chien, S. (2005) Molecular basis of the effects of shear stress on vascular endothelial cells. J. Biomech. 38, 1949–1971.PubMedCrossRefGoogle Scholar
  17. 17.
    Tarbell, J. M., Weinbaum, S., and Kamm, R. D. (2005) Cellular fluid mechanics and mechanotransduction. Ann. Biomed. Eng. 33, 1719–1723.PubMedCrossRefGoogle Scholar
  18. 18.
    Barakat, A. I., Lieu, D. K., and Gojova, A. (2006) Secrets of the code: do vascular endothelial cells use ion channels to decipher complex flow signals? Biomaterials 27, 671–678.PubMedCrossRefGoogle Scholar
  19. 19.
    Olesen, S. P., Clapham, D. E., and Davies, P. F. (1988) Haemodynamic shear stress activates a K+ current in vascular endothelial cells. Nature 331, 168–170.PubMedCrossRefGoogle Scholar
  20. 20.
    Nakache, M. and Gaub, H. E. (1988) Hydrodynamic hyperpolarization of endothelial cells. Proc. Natl. Acad. Sci. U. S. A. 85, 1841–1843.PubMedCrossRefGoogle Scholar
  21. 21.
    Jacobs, E. R., Cheliakine, C., Gebremedhin, D., Birks, E. K., Davies, P. F., and Harder, D. R. (1995) Shear activated channels in cell-attached patches of cultured bovine aortic endothelial cells. Pflugers Arch. 431, 129–131.PubMedCrossRefGoogle Scholar
  22. 22.
    Lieu, D. K., Pappone, P. A., and Barakat, A. I. (2004) Differential membrane potential and ion current responses to different types of shear stress in vascular endothelial cells. Am. J. Physiol. Cell Physiol. 286, C1367-C1375.PubMedCrossRefGoogle Scholar
  23. 23.
    Forsyth, S. E., Hoger, A., and Hoger, J. H. (1997) Molecular cloning and expression of a bovine endothelial inward rectifier potassium channel. FEBS Lett. 409, 277–282.PubMedCrossRefGoogle Scholar
  24. 24.
    Hoger, J. H., Ilyin, V. I., Forsyth, S., and Hoger, A. (2002) Shear stress regulates the endothelial Kir2.1 ion channel. Proc. Natl. Acad. Sci. U. S. A. 99, 7780–7785.PubMedCrossRefGoogle Scholar
  25. 25.
    Chatterjee, S., Al-Mehdi, A. B., Levitan, I., Stevens, T., and Fisher, A. B. (2003) Shear stress increases expression of a KATP channel in rat and bovine pulmonary vascular endothelial cells. Am. J. Physiol. Cell Physiol. 285, C959-C967.PubMedGoogle Scholar
  26. 26.
    Brakemeier, S., Kersten, A., Eichler, I., Grgic, I., Zakrzewicz, A., Hopp, H., Kohler, R., and Hoyer, J. (2003) Shear stress-induced up-regulation of the intermediate-conductance Ca2+-activated K+ channel in human endothelium. Cardiovasc. Res. 60, 488–496.PubMedCrossRefGoogle Scholar
  27. 27.
    Barakat, A. I., Leaver, E. V., Pappone, P. A., and Davies, P. F. (1999) A flow-activated chloride-selective membrane current in vascular endothelial cells. Circ. Res. 85, 820–828.PubMedGoogle Scholar
  28. 28.
    Nakao, M., Ono, K., Fujisawa, S., and Lijima, T. (1999) Mechanical stress-induced Ca2+ entry and Cl current in cultured human aortic endothelial cells. Am. J. Physiol. Cell Physiol. 276, C238-C249.Google Scholar
  29. 29.
    Romanenko, V. G., Davies, P. F., and Levitan, I. (2002) Dual effect of fluid shear stress on volume-regulated anion current in bovine aortic endothelial cells. Am. J. Physiol. Cell Physiol. 282, C708-C718.PubMedGoogle Scholar
  30. 30.
    Levitan, I., Christian, A. E., Tulenko, T. N., and Rothblat, G. H. (2000) Membrane cholesterol content modulates activation of volume-regulated anion current in bovine endothelial cells. J. Gen. Physiol. 115, 405–416.PubMedCrossRefGoogle Scholar
  31. 31.
    Schwarz, G., Droogmans, G., and Nilius, B. (1992) Shear stress induced membrane currents and calcium transients in human vascular endothelial cells. Pflugers Arch. 421, 394–396.PubMedCrossRefGoogle Scholar
  32. 32.
    Jow, F. and Numann, R. (1999) Fluid flow modulates calcium entry and activates membrane currents in cultured human aortic endothelial cells. J. Membr. Biol. 171, 127–139.PubMedCrossRefGoogle Scholar
  33. 33.
    Yamamoto, K., Korenaga, R., Kamiya, A., and Ando, J. (2000) Fluid shear stress activates Ca2+ influx into human end othelial cells via P2X4 purinoceptors. Circ. Res. 87, 385–391.PubMedGoogle Scholar
  34. 34.
    Yamamoto, K., Sokabe, T., Ohura, N., Nakatsuka, H., Kamiya, A., and Ando, J. (2003) Endogenously released ATP mediates shear stress-induced Ca2+ influx into pulmonary artery endothelial cells. Am. J. Physiol. Cell Physiol. 285, H793-H803.Google Scholar
  35. 35.
    Carattino, M. D., Sheng, S., and Kleyman, T. R., (2004) Epithelial Na+ channels are activated by laminar shear stress. J. Biol. Chem. 279, 4120–4126.PubMedCrossRefGoogle Scholar
  36. 36.
    Satlin, L. M., Sheng, S., Woda, C. B., and Kleyman, T. R. (2001) Epithelial Na+ channels are regulated by flow. Am. J. Physiol. Cell Physiol. 280, F1010-F1018.Google Scholar
  37. 37.
    Moccia, F., Villa, A., and Tanzi, F. (2000) Flow-activated Na+ and K+ Current in cardiac microvascular endothelial cells. J. Mol. Cell. Cardiol. 32, 1589–1593.PubMedCrossRefGoogle Scholar
  38. 38.
    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 endogeneous nitrovasodilator. J. Clin. Invest. 88, 1663–1671.PubMedGoogle Scholar
  39. 39.
    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.PubMedGoogle Scholar
  40. 40.
    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. Modulation by potassium channel blockade. J. Clin. Invest. 95, 1363–1369.PubMedGoogle Scholar
  41. 41.
    Uematsu, M., Ohara, Y., Navas, J. P., Nishida, K., Murphy, T. J., Alexander, R. W., Nerem, R. M., and Harrison, D. G. (1995) Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress. Am. J. Physiol. Cell Physiol. 269, C1371-C1378.Google Scholar
  42. 42.
    Malek, A. M. and Izumo, S. (1994) Molecular aspects of signal transduction of shear stress in the endothelial cell. J. Hypertens. 12, 989–999.PubMedCrossRefGoogle Scholar
  43. 43.
    Traub, O., Ishida, T., Ishida, M., Tupper, J. C., and Berk, B. C. (1999) Shear stress-mediated extracellular signal-regulated kinase activation is regulated by sodium in endothelial cells. Potential role for a voltage-dependent sodium channel. J. Biol. Chem. 274, 20144–20150.PubMedCrossRefGoogle Scholar
  44. 44.
    Suvatne, J., Barakat, A. I., and O'Donnell, M. E. (2001) Flow-induced expression of endothelial Na−K−Cl cotransport: dependence on K+ and Cl channels. Am. J. Physiol. Cell Physiol. 280, C216-C227.PubMedGoogle Scholar
  45. 45.
    Gojova, A. and Barakat, A. I. (2005) Vascular endothelial wound closure under shear stress: role of membrane fluidity and flow-sensitive ion channels. J. Appl. Physiol. 98, 2355–2362.PubMedCrossRefGoogle Scholar
  46. 46.
    Berridge, M. J., Bootman, M. D., and Roderick, H. L. (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat. Rev. Mol. Cell Biol. 4, 517–529.PubMedCrossRefGoogle Scholar
  47. 47.
    Hoyer, J., Kohler, R., and Distler, A. (1998) Mechanosensitive Ca2+ oscillations and STOC activation in endothelial cells. FASEB J. 12, 359–366.PubMedGoogle Scholar
  48. 48.
    Denk, W., Holt, J. R., Shepherd, G. M., and Corey, D. P. (1995) Calcium imaging of single stereocilia in hair cells: localization of transduction channels at both ends of tip links. Neuron 15, 1311–1321.PubMedCrossRefGoogle Scholar
  49. 49.
    Fettiplace, R. and Hackney, C. M. (2006) The sensory and motor roles of auditory hair cells. Nat. Rev. Neurosci. 7, 19–29.PubMedCrossRefGoogle Scholar
  50. 50.
    Hudspeth, A. J. (1989) How the ear's works work. Nature 341, 397–404.PubMedCrossRefGoogle Scholar
  51. 51.
    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.PubMedCrossRefGoogle Scholar
  52. 52.
    Hamill, O. P. and Martinac, B. (2001) Molecular basis of mechanotransduction in living cells. Physiol. Rev. 81, 685–740.PubMedGoogle Scholar
  53. 53.
    Bilston, L. E. and Mylvaganam, K. (2002) Molecular simulations of the large conductance mechanosensitive (MscL) channel under mechanical loading. FEBS Lett. 512, 185–190.PubMedCrossRefGoogle Scholar
  54. 54.
    Chang, G., Spencer, R. H., Lee, A. T., Barclay, M. T., and Rees, D. C. (1998) Structure of the MscL homolog, from Mycobacterium tuberculosis: a gated mechanosensitive ion channel. Science 282, 2220–2226.PubMedCrossRefGoogle Scholar
  55. 55.
    Gullingsrud, J., Kosztin, D., and Schulten, K. (2001) Structural determinants of MscL gating studied by molecular dynamics simulations. Biophys. J. 80, 2074–2081.PubMedGoogle Scholar
  56. 56.
    Fung, Y. C., and Liu, S. Q. (1993) Elementary mechanics of the endothelium of blood vessels. J. Biomech. Eng. 115, 1–12.PubMedGoogle Scholar
  57. 57.
    Moe, P. and Blount, P. (2005) Assessment of potential stimuli for mechano-dependent gating of MscL: effects of pressure, tension, and lipid headgroups. Biochemistry 44, 12239–12244.PubMedCrossRefGoogle Scholar
  58. 58.
    Sukharev, S. (1999) Mechanosensitive channels in bacteria as membrane tension reporters. FASEB J. 13, S55-S61.PubMedGoogle Scholar
  59. 59.
    Charras, G. T., Williams, B. A., Sims, S. M., and Horton, M. A. (2004) Estimating the sensitivity of mechanosensitive ion channels to membrane strain and tension. Biophys. J. 87, 2870–2884.PubMedCrossRefGoogle Scholar
  60. 60.
    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. Cell Physiol. 280, C962-C969.PubMedGoogle Scholar
  61. 61.
    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. Cell Physiol. 278, H1401-H1406.Google Scholar
  62. 62.
    Romanenko, V. G., Rothblat, G. H., and Levitan, I. (2002) Modulation of endothelial inward-rectifier K+ current by optical isomers of cholesterol. Biophys. J. 83, 3211–3222.PubMedCrossRefGoogle Scholar
  63. 63.
    Li, X. A., Everson, W. V., and Smart, E. J. (2005) Caveolae, lipid rafts, and vascular disease. Trends Cardiovasc Med. 15, 92–96.PubMedCrossRefGoogle Scholar
  64. 64.
    Simons, K. and Ehehalt, R. (2002) Cholesterol, lipid rafts, and disease. J. Clin. Invest. 110, 597–603.PubMedCrossRefGoogle Scholar
  65. 65.
    Simons, K. and Toomre, D. (2000) Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol. 1, 31–39.PubMedCrossRefGoogle Scholar
  66. 66.
    Yang, B., Oo, T. N., and Rizzo, V. (2006) Lipid rafts mediate H2O2 prosurvival effects in cultured endothelial cells. FASEB J. 20, 1501–1503.PubMedCrossRefGoogle Scholar
  67. 67.
    Thi, M. M., Tarbell, J. M., Weinbaum, S., and Spray, D. C. (2004) The role of the glycocalyx in reorganization of the actin cytoskeleton under fluid shear stress: a “bumper-car” model. Proc. Natl. Acad. Sci. U. S. A. 101, 16483–16488.PubMedCrossRefGoogle Scholar
  68. 68.
    Weinbaum, S., Zhang, X., Han, Y., Vink, H., and Cowin, S. C. (2003) Mechanotransduction and flow across the endothelial glycocalyx. Proc. Natl. Acad. Sci. U. S. A. 100, 7988–7995.PubMedCrossRefGoogle Scholar
  69. 69.
    Sachs, F. and Morris, C. E. (1998) Mechanosensitive ion channels in nonspecialized cells. Rev. Physiol. Biochem. Pharmacol. 132, 1–77.PubMedCrossRefGoogle Scholar
  70. 70.
    Hamill, O. P. and McBride, D. W., Jr. (1997) Mechanogated channels in Xenopus oocytes: different gating modes enable a channel to switch from a phasic to a tonic mechanotransducer. Biol. Bull. 192, 121–122.PubMedCrossRefGoogle Scholar
  71. 71.
    Zhang, Q., Matsuzaki, I., Chatterjee, S., and Fisher, A. B. (2005) Activation of endothelial NADPH oxidase during normoxic lung ischemia is KATP channel dependent. Am. J. Physiol. Lung Cell Mol. Physiol. 289, L954-L961.PubMedCrossRefGoogle Scholar
  72. 72.
    Matsuzaki, I., Chatterjee, S., Debolt, K., Manevich, Y., Zhang, Q., and Fisher, A. B. (2005) Membrane depolarization and NADPH oxidase activation in aortic endothelium during ischemia reflect altered mechanotransduction. Am. J. Physiol. Heart Circ. Physiol. 288, H336-H343.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2006

Authors and Affiliations

  • Mamta Gautam
    • 1
  • Andrea Gojova
    • 1
  • Abdul I. Barakat
    • 1
  1. 1.Department of Mechanical and Aeronautical EngineeringUniversity of CaliforniaDavis

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