Skip to main content

Advertisement

SpringerLink
Log in

Cellular signaling and NO production

  • Signaling and Cell Physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

The endothelium can evoke relaxations (dilatations) of the underlying vascular smooth muscle, by releasing vasodilator substances. The best characterized endothelium-derived relaxing factor is nitric oxide (NO), which is synthesized by the endothelial isoform of nitric oxide synthase (eNOS). Endothelium-dependent relaxations involve both pertussis-toxin-sensitive Gi (e.g., responses to serotonin, sphingosine 1-phosphate, alpha2-adrenergic agonists, and thrombin) and pertussis-toxin-insensitive Gq (e.g., adenosine diphosphate and bradykinin) coupling proteins. eNOS undergoes a complex pattern of intracellular regulation, including post-translational modifications involving enzyme acylation and phosphorylation. eNOS is reversibly targeted to signal-transducing plasmalemmal caveolae where the enzyme interacts with a number of regulatory proteins, many of which are modified in cardiovascular disease states. The release of nitric oxide by the endothelial cell can be up- (e.g., by estrogens, exercise, and dietary factors) and down-regulated (e.g. oxidative stress, smoking, and oxidized low-density lipoproteins). It is reduced in the course of vascular disease (e.g., diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis-toxin-sensitive pathway for NO release which favors vasospasm, thrombosis, penetration of macrophages, cellular growth, and the inflammatory reaction leading to atherosclerosis. The unraveling of the complex interaction of the pathways regulating the presence and the activity of eNOS will enhance the understanding of the perturbations in endothelium-dependent signaling that are seen in cardiovascular disease states, and may lead to the identification of novel targets for therapeutic intervention.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Aikawa M, Libby P (2004) The vulnerable atherosclerotic plaque pathogenesis and therapeutic approach. Cardiovasc Path 13:125–138

    Article  Google Scholar 

  2. Balligand JL, Feron O et al (2009) eNOS activation by physical forces: from short-term regulation of contraction to chronic remodeling of cardiovascular tissues. Physiol Rev 89(2):481–534

    Article  CAS  PubMed  Google Scholar 

  3. Berka V, Wu G, Yeh HC et al (2004) Three different oxygen-induced radical species in endothelial nitric-oxide synthase oxygenase domain under regulation by L-arginine and tetrahydrobiopterin. J Biol Chem 279:32243–32251

    Article  CAS  PubMed  Google Scholar 

  4. Busse R, Edwards G, Félétou M, Fleming I, Vanhoutte PM (2002) EDHF: bringing the concepts together. Trends Pharmacol Sci 23:374–380

    Article  CAS  PubMed  Google Scholar 

  5. Busse R, Fleming I (2003) Regulation of endothelium-derived vasoactive autacoid production by hemodynamic forces. Trends Pharmacol Sci 24:24–29

    Article  CAS  PubMed  Google Scholar 

  6. Cai H (2005) Hydrogen peroxide regulation of endothelial function: origins, mechanisms, and consequences. Cardiovasc Res 68(1):26–36

    Article  CAS  PubMed  Google Scholar 

  7. Cai H, Griendling KK et al (2003) The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci 24(9):471–478

    Article  CAS  PubMed  Google Scholar 

  8. Chen Z, Peng IC et al (2009) AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633. Circ Res 104(4):496–505

    Article  CAS  PubMed  Google Scholar 

  9. Davies PF (1995) Flow-mediated endothelial mechanotransduction. Physiol Rev 75:519–560

    CAS  PubMed  Google Scholar 

  10. De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM (2000) Endothelial dysfunction in diabetes. Br J Pharmacol 130:963–974

    Article  PubMed  Google Scholar 

  11. Deanfield JE, Halcox JP et al (2007) Endothelial function and dysfunction: testing and clinical relevance. Circulation 115(10):1285–1295

    PubMed  Google Scholar 

  12. Dudzinski DM, Michel T (2007) Life history of eNOS: partners and pathways. Cardiovasc Res 75(2):247–260

    Article  CAS  PubMed  Google Scholar 

  13. Dudzinski DM, Igarashi J et al (2006) The regulation and pharmacology of endothelial nitric oxide synthase. Annu Rev Pharmacol Toxicol 46:235–276

    Article  CAS  PubMed  Google Scholar 

  14. Erwin PA, Lin AJ et al (2005) Receptor-regulated dynamic S-nitrosylation of endothelial nitric-oxide synthase in vascular endothelial cells. J Biol Chem 280(20):19888–19894

    Article  CAS  PubMed  Google Scholar 

  15. Erwin PA, Mitchell DA et al (2006) Subcellular targeting and differential S-nitrosylation of endothelial nitric-oxide synthase. J Biol Chem 281(1):151–157

    Article  CAS  PubMed  Google Scholar 

  16. Félétou M, Vanhoutte PM (2006) EDHF: the complete story. CRC Taylor and Francis, Boca Raton, pp 1–298

    Google Scholar 

  17. Félétou M, Vanhoutte PM (2006) Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture). Am J Physiol Heart Circ Physiol 291:H985–H1002

    Article  PubMed  Google Scholar 

  18. Félétou M, Vanhoutte PM (2009) EDHF: an update. Clin Sci 117(4):139–55

    Google Scholar 

  19. Feron O, Balligand JL (2006) Caveolins and the regulation of endothelial nitric oxide synthase in the heart. Cardiovasc Res 69(4):788–797

    Article  CAS  PubMed  Google Scholar 

  20. Feron O, Saldana F et al (1998) The endothelial nitric-oxide synthase-caveolin regulatory cycle. J Biol Chem 273(6):3125–3128

    Article  CAS  PubMed  Google Scholar 

  21. Fisslthaler B, Loot AE, Mohamed A, Busse R, Fleming I (2008) Inhibition of endothelial nitric oxide synthase activity by proline-rich tyrosine kinase 2 in response to fluid shear stress and insulin. Circ Res 102:1520–1528

    Article  CAS  PubMed  Google Scholar 

  22. Fisslthaler B, Fleming I (2009) Activation and signaling by the AMP-activated protein kinase in endothelial cells. Circ Res 105(2):114–127

    Article  CAS  PubMed  Google Scholar 

  23. Fleming I, Busse R (2003) Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol 284:R1–R12

    CAS  PubMed  Google Scholar 

  24. Forstermann U, Boissel J-P, Kleinert J (1998) Expressional control of the ‘constitutive’ isoforms of nitric oxide synthase. FASEB J 12:773–790

    CAS  PubMed  Google Scholar 

  25. Fulton D, Church JE et al (2005) Src kinase activates endothelial nitric-oxide synthase by phosphorylating Tyr-83. J Biol Chem 280(43):35943–35952

    Article  CAS  PubMed  Google Scholar 

  26. Fulton D, Gratton JP et al (2001) Post-translational control of endothelial nitric oxide synthase: why isn't calcium/calmodulin enough? J Pharmacol Exp Ther 299(3):818–824

    CAS  PubMed  Google Scholar 

  27. Furchgott RF, Vanhoutte PM (1989) Endothelium-derived relaxing and contracting factors. FASEB J 3:2007–2017

    CAS  PubMed  Google Scholar 

  28. Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376

    Article  CAS  PubMed  Google Scholar 

  29. Furuhashi M, Hotamisligil GS (2008) Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev 7:489–503

    Article  CAS  Google Scholar 

  30. Gonzalez E, Nagiel A et al (2004) Small interfering RNA-mediated down-regulation of caveolin-1 differentially modulates signaling pathways in endothelial cells. J Biol Chem 279(39):40659–40669

    Article  CAS  PubMed  Google Scholar 

  31. Govers R, Rabelink TJ (2001) Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol 280(2):F193–F206

    CAS  PubMed  Google Scholar 

  32. Gratton JP, Bernatchez P et al (2004) Caveolae and caveolins in the cardiovascular system. Circ Res 94(11):1408–1417

    Article  CAS  PubMed  Google Scholar 

  33. Harrison DG (1997) Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest 100(9):2153–2157

    Article  CAS  PubMed  Google Scholar 

  34. Hess DT, Matsumoto A et al (2005) Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol 6(2):150–166

    Article  CAS  PubMed  Google Scholar 

  35. Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M et al (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88(2):E14–E22

    CAS  PubMed  Google Scholar 

  36. Hla T, Lee MJ et al (2001) Lysophospholipids–receptor revelations. Science 294(5548):1875–1878

    Article  CAS  PubMed  Google Scholar 

  37. Icking A, Matt S et al (2005) NOSTRIN functions as a homotrimeric adaptor protein facilitating internalization of eNOS. J Cell Sci 118(Pt 21):5059–5069

    Article  CAS  PubMed  Google Scholar 

  38. Jain MK, Ridker PM (2005) Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov 4(12):977–987

    Article  CAS  PubMed  Google Scholar 

  39. Katusic ZS (2001) Vascular endothelial dysfunction: does tetrahydrobiopterin play a role? Am J Physiol Heart Circ Physiol 281(3):H981–H986

    CAS  PubMed  Google Scholar 

  40. Katusic ZS, d'Uscio LV et al (2009) Vascular protection by tetrahydrobiopterin: progress and therapeutic prospects. Trends Pharmacol Sci 30(1):48–54

    Article  CAS  PubMed  Google Scholar 

  41. Katusic ZS (2007) Mechanisms of endothelial dysfunction induced by aging: role of arginase I. Circ Res 101:640–641

    Article  CAS  PubMed  Google Scholar 

  42. Kojda G, Harrison D (1999) Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure. Cardiovasc Res 43:562–571

    Article  CAS  PubMed  Google Scholar 

  43. Konig P, Dedio J et al (2005) NOSIP and its interacting protein, eNOS, in the rat trachea and lung. J Histochem Cytochem 53(2):155–164

    Article  PubMed  Google Scholar 

  44. Lee MYK, Tse HF, Siu CW, Zhu SG, Man RYK, Vanhoutte PM (2007) Genomic changes in regenerated porcine coronary arterial endothelial cells. Arterioscler Thromb Vasc Biol 27:2443–2449

    Article  CAS  PubMed  Google Scholar 

  45. Levine YC, Li GK et al (2007) Agonist-modulated regulation of AMP-activated protein kinase (AMPK) in endothelial cells. Evidence for an AMPK -> Rac1 -> Akt -> endothelial nitric-oxide synthase pathway. J Biol Chem 282(28):20351–20364

    Article  CAS  PubMed  Google Scholar 

  46. Li JM, Shah AM (2004) Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 287(5):R1014–R1030

    CAS  PubMed  Google Scholar 

  47. Li PL, Gulbins E (2007) Lipid rafts and redox signaling. Antioxid Redox Signal 9(9):1411–1415

    Article  CAS  PubMed  Google Scholar 

  48. Loscalzo J, Welch G (1995) Nitric oxide and its role in the cardiovascular system. Prog Cardiovasc Dis 38(2):87–104

    Article  CAS  PubMed  Google Scholar 

  49. Lubos E, Handy DE et al (2008) Role of oxidative stress and nitric oxide in atherothrombosis. Front Biosci 13:5323–5344

    Article  CAS  PubMed  Google Scholar 

  50. Lüscher TF, Vanhoutte PM (1990) The endothelium: modulator of cardiovascular function. CRC, Boca Raton, pp 1–228

    Google Scholar 

  51. Martinez-Ruiz A, Villanueva L et al (2005) S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc Natl Acad Sci USA 102:8525–8530

    Article  CAS  PubMed  Google Scholar 

  52. Miller VM, Duckles SP (2008) Vascular actions of estrogens: functional implications. Pharmacol Rev 60:210–241

    Article  CAS  PubMed  Google Scholar 

  53. Miller VM, Vanhoutte PM (1988) Enhanced release of endothelium-derived factors by chronic increases in blood flow. Am J Physiol 255:H446–H451

    CAS  PubMed  Google Scholar 

  54. Miller VM, Vanhoutte PM (1991) Progesterone and modulation of endothelium-dependent responses in canine coronary arteries. Am J Physiol 261:R1022–R1027

    CAS  PubMed  Google Scholar 

  55. Moens AL, Kass DA (2006) Tetrahydrobiopterin and cardiovascular disease. Arterioscler Thromb Vasc Biol 26(11):2439–2444

    Article  CAS  PubMed  Google Scholar 

  56. Moncada S (1997) Nitric oxide in the vasculature: physiology and pathophysiology. Ann N Y Acad Sci 811:60–67

    Article  CAS  PubMed  Google Scholar 

  57. Radi R (2004) Nitric oxide, oxidations, and protein tyrosine nitration. Proc Natl Acad Sci USA 101:4003–4008

    Article  CAS  PubMed  Google Scholar 

  58. Rubanyi GM, Vanhoutte PM (1986) Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor(s). Am J Physiol 250:H822–H827

    CAS  PubMed  Google Scholar 

  59. Rubanyi GM, Lorenz RR, Vanhoutte PM (1985) Bioassay of endothelium-derived relaxing factor(s). Inactivation by catecholamines. Am J Physiol 249:H95–H101

    CAS  PubMed  Google Scholar 

  60. Rubanyi GM, Romero JC, Vanhoutte PM (1986) Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 250:H1145–H1149

    CAS  PubMed  Google Scholar 

  61. Schilling K, Opitz N et al (2006) Translocation of endothelial nitric-oxide synthase involves a ternary complex with caveolin-1 and NOSTRIN. Mol Biol Cell 17(9):3870–3880

    Article  CAS  PubMed  Google Scholar 

  62. Schroder E, Eaton P (2008) Hydrogen peroxide as an endogenous mediator and exogenous tool in cardiovascular research: issues and considerations. Curr Opin Pharmacol 8(2):153–159

    Article  PubMed  Google Scholar 

  63. Sessa WC (2004) eNOS at a glance. J Cell Sci 117(Pt 12):2427–2429

    Article  CAS  PubMed  Google Scholar 

  64. Shaul PW (2002) Regulation of endothelial nitric oxide synthase: location, location, location. Annu Rev Physiol 64:749–774

    Article  CAS  PubMed  Google Scholar 

  65. Shaul PW (2003) Endothelial nitric oxide synthase, caveolae and the development of atherosclerosis. J Physiol 547(Pt 1):21–33

    Article  CAS  PubMed  Google Scholar 

  66. Skidgel RA (2002) Proliferation of regulatory mechanisms for eNOS: an emerging role for the cytoskeleton. Am J Physiol Lung Cell Mol Physiol 282(6):L1179–L1182

    CAS  PubMed  Google Scholar 

  67. Stamler JS, Lamas S, Fang FC (2001) Nitrosylation: the prototypic redox-based signaling mechanism. Cell 106:675–683

    Article  CAS  PubMed  Google Scholar 

  68. Steuhr DJ (1997) Structure-function aspects in the nitric oxide synthases. Ann Rev Pharmacol Toxicol 37:339–359

    Article  Google Scholar 

  69. Stocker R, Keaney JF Jr (2004) Role of oxidative modifications in atherosclerosis. Physiol Rev 84:1381–1478

    Article  CAS  PubMed  Google Scholar 

  70. Su Y, Edwards-Bennett S et al (2003) Regulation of endothelial nitric oxide synthase by the actin cytoskeleton. Am J Physiol Cell Physiol 284(6):C1542–C1549

    CAS  PubMed  Google Scholar 

  71. Thomas SR, Witting PK et al (2008) Redox control of endothelial function and dysfunction: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 10(10):1713–1765

    Article  CAS  PubMed  Google Scholar 

  72. Vanhoutte PM (2008) Arginine and arginase: eNOS double crossed? Circ Res 102:866–868

    Article  CAS  PubMed  Google Scholar 

  73. Vanhoutte PM, Tang EHC (2008) Endothelium-dependent contractions: when a good guy turns bad. J Physiol 586:5295–5303

    Article  CAS  PubMed  Google Scholar 

  74. Vanhoutte PM (2009) How we learned to say NO. Arterioscl Thromb Vasc Biol 29:1156–1160

    Article  CAS  PubMed  Google Scholar 

  75. Vanhoutte PM, Félétou M, Taddei S (2005) Endothelium-dependent contractions in hypertension. Br J Pharmacol 144:449–458

    Article  CAS  PubMed  Google Scholar 

  76. Vanhoutte PM, Shimokawa H, Tang EHC, Félétou M (2009) Endothelial dysfunction and vascular disease. Acta Physiol 196:193–222

    Article  CAS  Google Scholar 

  77. Wolin MS (2009) Reactive oxygen species and the control of vascular function. Am J Physiol Heart Circ Physiol 296(3):H539–H549

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

The authors thank Mr. Robert R. Lorenz for the expert help in preparing the figures.

Author information

Authors and Affiliations

  1. Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Thomas Michel

  2. Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

    Paul M. Vanhoutte

Authors
  1. Thomas Michel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul M. Vanhoutte
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Michel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Michel, T., Vanhoutte, P.M. Cellular signaling and NO production. Pflugers Arch - Eur J Physiol 459, 807–816 (2010). https://doi.org/10.1007/s00424-009-0765-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-009-0765-9

Keywords

Search

Navigation