Endothelial nitric oxide synthase in the microcirculation

Abstract

Endothelial nitric oxide synthase (eNOS, NOS3) is responsible for producing nitric oxide (NO)—a key molecule that can directly (or indirectly) act as a vasodilator and anti-inflammatory mediator. In this review, we examine the structural effects of regulation of the eNOS enzyme, including post-translational modifications and subcellular localization. After production, NO diffuses to surrounding cells with a variety of effects. We focus on the physiological role of NO and NO-derived molecules, including microvascular effects on vessel tone and immune response. Regulation of eNOS and NO action is complicated; we address endogenous and exogenous mechanisms of NO regulation with a discussion of pharmacological agents used in clinical and laboratory settings and a proposed role for eNOS in circulating red blood cells.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. 1.

    Roman LJ, Martásek P, Masters BS (2002) Intrinsic and extrinsic modulation of nitric oxide synthase activity. Chem Rev 102:1179–1190

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Volkmann N, Martásek P, Roman LJ, Xu XP, Page C, Swift M, Hanein D, Masters BS (2014) Holoenzyme structures of endothelial nitric oxide synthase—an allosteric role for calmodulin in pivoting the FMN domain for electron transfer. J Struct Biol 188:46–54

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  3. 3.

    Piazza M, Taiakina V, Guillemette SR, Guillemette JG, Dieckmann T (2014) Solution structure of calmodulin bound to the target peptide of endothelial nitric oxide synthase phosphorylated at Thr495. Biochemistry 53:1241–1249

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Crane BR, Arvai AS, Ghosh DK, Wu C, Getzoff ED, Stuehr DJ, Tainer JA (1998) Structure of nitric oxide synthase oxygenase dimer with pterin and substrate. Science 279:2121–2126

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Chen PF, Tsai AL, Wu KK (1994) Cysteine 184 of endothelial nitric oxide synthase is involved in heme coordination and catalytic activity. J Biol Chem 269:25062–25066

    CAS  PubMed  Google Scholar 

  6. 6.

    Chen PF, Tsai AL, Wu KK (1995) Cysteine 99 of endothelial nitric oxide synthase (NOS-III) is critical for tetrahydrobiopterin-dependent NOS-III stability and activity. Biochem Biophys Res Commun 215:1119–1129

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Fischmann TO, Hruza A, Niu XD, Fossetta JD, Lunn CA, Dolphin E, Prongay AJ, Reichert P, Lundell DJ, Narula SK, Weber PC (1999) Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation. Nat Struct Biol 6:233–242

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Hellermann GR, Solomonson LP (1997) Calmodulin promotes dimerization of the oxygenase domain of human endothelial nitric-oxide synthase. J Biol Chem 272:12030–12034

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Lane P, Gross SS (2000) The autoinhibitory control element and calmodulin conspire to provide physiological modulation of endothelial and neuronal nitric oxide synthase activity. Acta Physiol Scand 168:53–63

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Lane P, Gross SS (2002) Disabling a C-terminal autoinhibitory control element in endothelial nitric-oxide synthase by phosphorylation provides a molecular explanation for activation of vascular NO synthesis by diverse physiological stimuli. J Biol Chem 277:19087–19094

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Garcin ED, Bruns CM, Lloyd SJ, Hosfield DJ, Tiso M, Gachhui R, Stuehr DJ, Tainer JA, Getzoff ED (2004) Structural basis for isozyme-specific regulation of electron transfer in nitric-oxide synthase. J Biol Chem 279:37918–37927

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Prabhakar P, Cheng V, Michel T (2000) A chimeric transmembrane domain directs endothelial nitric-oxide synthase palmitoylation and targeting to plasmalemmal caveolae. J Biol Chem 275:19416–19421

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Fernández-Hernando C, Fukata M, Bernatchez PN, Fukata Y, Lin MI, Bredt DS, Sessa WC (2006) Identification of Golgi-localized acyl transferases that palmitoylate and regulate endothelial nitric oxide synthase. J Cell Biol 174:369–377

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  14. 14.

    Segal SS, Brett SE, Sessa WC (1999) Codistribution of NOS and caveolin throughout peripheral vasculature and skeletal muscle of hamsters. Am J Physiol 277:1167–1177

    Google Scholar 

  15. 15.

    Ju H, Zou R, Venema VJ, Venema RC (1997) Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity. J Biol Chem 272:18522–18525

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Xu H, Shi Y, Wang J, Jones D, Weilrauch D, Ying R, Wakim B, Pritchard KA (2007) A heat shock protein 90 binding domain in endothelial nitric-oxide synthase influences enzyme function. J Biol Chem 282:37567–37574

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Lin MI, Fulton D, Babbitt R, Fleming I, Busse R, Pritchard KA, Sessa WC (2003) Phosphorylation of threonine 497 in endothelial nitric-oxide synthase coordinates the coupling of l-arginine metabolism to efficient nitric oxide production. J Biol Chem 278:44719–44726

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Takahashi S, Mendelsohn ME (2003) Synergistic activation of endothelial nitric-oxide synthase (eNOS) by HSP90 and Akt: calcium-independent eNOS activation involves formation of an HSP90-Akt-CaM-bound eNOS complex. J Biol Chem 278:30821–30827

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Dedio J, König P, Wohlfart P, Schroeder C, Kummer W, Müller-Esterl W (2001) NOSIP, a novel modulator of endothelial nitric oxide synthase activity. FASEB J. 15:79–89

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Matsumoto K, Nishiya T, Maekawa S, Horinouchi T, Ogasawara K, Uehara T, Miwa S (2011) The ECS(SPSB) E3 ubiquitin ligase is the master regulator of the lifetime of inducible nitric-oxide synthase. Biochem Biophys Res Commun 409:46–51

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Kondrikov D, Elms S, Fulton D, Su Y (2010) eNOS-beta-actin interaction contributes to increased peroxynitrite formation during hyperoxia in pulmonary artery endothelial cells and mouse lungs. J Biol Chem 285:35479–35487

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  22. 22.

    Kondrikov D, Fonseca FV, Elms S, Fulton D, Black SM, Block ER, Su Y (2010) Beta-actin association with endothelial nitric-oxide synthase modulates nitric oxide and superoxide generation from the enzyme. J Biol Chem 285:4319–4327

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  23. 23.

    Matsuda N, Hayashi Y, Takahashi Y, Hattori Y (2006) Phosphorylation of endothelial nitric-oxide synthase is diminished in mesenteric arteries from septic rabbits depending on the altered phosphatidylinositol 3-kinase/Akt pathway: reversal effect of fluvastatin therapy. J Pharmacol Exp Ther 319:1348–1354

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Kone BC, Kuncewicz T, Zhang W, Yu ZY (2003) Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide. Am J Physiol Renal Physiol. 285:F178–F190

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Straub AC, Butcher JT, Billaud M, Mutchler SM, Artamonov MV, Nguyen AT, Johnson T, Best AK, Miller MP, Palmer LA, Columbus L, Somlyo AV, Le TH, Isakson BE (2014) Hemoglobin alpha/eNOS coupling at myoendothelial junctions is required for nitric oxide scavenging during vasoconstriction. Arterioscler Thromb Vasc Biol 34:2594–2600

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  26. 26.

    Butcher JT, Johnson T, Beers J, Columbus L, Isakson BE (2014) Hemoglobin alpha in the blood vessel wall. Free Radic Biol Med 73:136–142

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H (2014) An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 96:253–262

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Michell BJ, Harris MB, Chen ZP, Ju H, Venema VJ, Blackstone MA, Huang W, Venema RC, Kemp BE (2002) Identification of regulatory sites of phosphorylation of the bovine endothelial nitric-oxide synthase at serine 617 and serine 635. J Biol Chem 277:42344–42351

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Harris MB, Blackstone MA, Sood SG, Li C, Goolsby JM, Venema VJ, Kemp BE, Venema RC (2004) Acute activation and phosphorylation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors. Am J Physiol Heart Circ Physiol 287:H560–H566

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Bauer PM, Fulton D, Boo YC, Sorescu GP, Kemp BE, Jo H, Sessa WC (2003) Compensatory phosphorylation and protein-protein interactions revealed by loss of function and gain of function mutants of multiple serine phosphorylation sites in endothelial nitric-oxide synthase. J Biol Chem 278:14841–14849

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Boo YC, Sorescu GP, Bauer PM, Fulton D, Kemp BE, Harrison DG, Sessa WC, Jo H (2003) Endothelial NO synthase phosphorylated at SER635 produces NO without requiring intracellular calcium increase. Free Radic Biol Med 35:729–741

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Boo YC, Sorescu G, Boyd N, Shiojima I, Walsh K, Du J, Jo H (2002) Shear stress stimulates phosphorylation of endothelial nitric-oxide synthase at Ser1179 by Akt-independent mechanisms: role of protein kinase A. J Biol Chem 277:3388–3396

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Harris MB, Ju H, Venema VJ, Liang H, Zou R, Michell BJ, Chen ZP, Kemp BE, Venema RC (2001) Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation. J Biol Chem 276:16587–16591

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Montagnani M, Chen H, Barr VA, Quon MJ (2001) Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser (1179). J Biol Chem 276:30392–30398

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Mount PF, Kemp BE, Power DA (2007) Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J Mol Cell Cardiol 42:271–279

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Drew BG, Fidge NH, Gallon-Beaumier G, Kemp BE, Kingwell BA (2004) High-density lipoprotein and apolipoprotein AI increase endothelial NO synthase activity by protein association and multisite phosphorylation. Proc Natl Acad Sci USA 101:6999–7004

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  37. 37.

    Fulton D, Church JE, Ruan L, Li C, Sood SG, Kemp BE, Jennings IG, Venema RC (2005) Src kinase activates endothelial nitric-oxide synthase by phosphorylating Tyr-83. J Biol Chem 280:35943–35952

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Fulton D, Ruan L, Sood SG, Li C, Zhang Q, Venema RC (2008) Agonist-stimulated endothelial nitric oxide synthase activation and vascular relaxation. Role of eNOS phosphorylation at Tyr83. Circ Res 102:497–504

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Kou R, Greif D, Michel T (2002) Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor. Implications for the vascular responses to cyclosporin A. J Biol Chem 277:29669–29673

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Heiss EH, Dirsch VM (2014) Regulation of eNOS enzyme activity by posttranslational modification. Curr Pharm Des 20:3503–3513

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  41. 41.

    Kolluru GK, Siamwala JH, Chatterjee S (2010) eNOS phosphorylation in health and disease. Biochimie 92:1186–1198

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Li C, Ruan L, Sood SG, Papapetropoulos A, Fulton D, Venema RC (2007) Role of eNOS phosphorylation at Ser-116 in regulation of eNOS activity in endothelial cells. Vascul Pharmacol 47:257–264

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  43. 43.

    Ruan L, Torres CM, Qian J, Chen F, Mintz JD, Stepp DW, Fulton D, Venema RC (2011) Pin1 prolyl isomerase regulates endothelial nitric oxide synthase. Arterioscler Thromb Vasc Biol 31:392–398

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  44. 44.

    Michell BJ, Zp Chen, Tiganis T, Stapleton D, Katsis F, Power DA, Sim AT, Kemp BE (2001) Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase. J Biol Chem 276:17625–17628

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Chen ZP, Mitchelhill KI, Michell BJ, Stapleton D, Rodriguez-Crespo I, Witters LA, Power DA, Ortiz de Montellano PR, Kemp BE (1999) AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett 443:285–289

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Matsubara M, Hayashi N, Jing T, Titani K (2003) Regulation of endothelial nitric oxide synthase by protein kinase C. J Biochem 133:773–781

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Aoyagi M, Arvai AS, Tainer JA, Getzoff ED (2003) Structural basis for endothelial nitric oxide synthase binding to calmodulin. EMBO J 22:766–775

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  48. 48.

    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

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Fleming I, Fisslthaler B, Dimmeler S, Kemp BE, Busse R (2001) Phosphorylation of Thr(495) regulates Ca(2+)/calmodulin-dependent endothelial nitric oxide synthase activity. Circ Res 88:E68–E75

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Loot AE, Schreiber JG, Fisslthaler B, Fleming I (2009) Angiotensin II impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase. J Exp Med 206:2889–2896

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  51. 51.

    Nathan C (1992) Nitric oxide as a secretory product of mammalian cells. FASEB J Off Publ Fed Am Soc Exp Biol 6:3051–3064

    CAS  Google Scholar 

  52. 52.

    Billaud M, Lohman AW, Johnstone SR, Biwer LA, Mutchler S, Isakson BE (2014) Regulation of cellular communication by signaling microdomains in the blood vessel wall. Pharmacol Rev 66:513–569

    PubMed Central  PubMed  Article  Google Scholar 

  53. 53.

    Prabhakar P, Thatte HS, Goetz RM, Cho MR, Golan DE, Michel T (1998) Receptor-regulated translocation of endothelial nitric-oxide synthase. J Biol Chem 273:27383–27388

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Sessa WC, Barber CM, Lynch KR (1993) Mutation of N-myristoylation site converts endothelial cell nitric oxide synthase from a membrane to a cytosolic protein. Circ Res 72:921–924

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Garcia-Cardena G, Oh P, Liu J, Schnitzer JE, Sessa WC (1996) Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. Proc Natl Acad Sci USA 93:6448–6453

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  56. 56.

    Shaul PW, Smart EJ, Robinson LJ, German Z, Yuhanna IS, Ying Y, Anderson RG, Michel T (1996) Acylation targets emdothelial nitric-oxide synthase to plasmalemmal caveolae. J Biol Chem 271:6518–6522

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Liu J, Garcia-Cardena G, Sessa WC (1996) Palmitoylation of endothelial nitric oxide synthase is necessary for optimal stimulated release of nitric oxide: implications for caveolae localization. Biochemistry 35:13277–13281

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Blair A, Shaul PW, Yuhanna IS, Conrad PA, Smart EJ (1999) Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation. J Biol Chem 274:32512–32519

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Igarashi J, Thatte HS, Prabhakar P, Golan DE, Michel T (1999) Calcium-independent activation of endothelial nitric oxide synthase by ceramide. Proc Natl Acad Sci USA 96:12583–12588

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  60. 60.

    Sessa WC, Garcia-Cardena G, Liu J, Keh A, Pollock JS, Bradley J, Thiru S, Braverman IM, Desai KM (1995) The Golgi association of endothelial nitric oxide synthase is necessary for the efficient synthesis of nitric oxide. J Biol Chem 270:17641–17644

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Fulton D, Babbitt R, Zoellner S, Fontana J, Acevedo L, McCabe TJ, Iwakiri Y, Sessa WC (2004) Targeting of endothelial nitric-oxide synthase to the cytoplasmic face of the Golgi complex or plasma membrane regulates Akt- versus calcium-dependent mechanisms for nitric oxide release. J Biol Chem 279:30349–30357

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Andries LJ, Brutsaert DL, Sys SU (1998) Nonuniformity of endothelial constitutive nitric oxide synthase distribution in cardiac endothelium. Circ Res 82:195–203

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Wagner L, Hoey JG, Erdely A, Boegehold MA, Baylis C (2001) The nitric oxide pathway is amplified in venular vs arteriolar cultured rat mesenteric endothelial cells. Microvasc Res 62:401–409

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Broeders MA, Tangelder GJ, Slaaf DW, Reneman RS, oude Egbrink MG (1998) Endogenous nitric oxide protects against thromboembolism in venules but not in arterioles. Arterioscler Thromb Vasc Biol 18:139–145

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Bakker EN, Sipkema P (1997) Components of acetylcholine-induced dilation in isolated rat arterioles. Am J Physiol 273:H1848–H1853

    CAS  PubMed  Google Scholar 

  66. 66.

    Billaud M, Lohman AW, Straub AC, Parpaite T, Johnstone SR, Isakson BE (2012) Characterization of the thoracodorsal artery: morphology and reactivity. Microcirculation 19:360–372

    PubMed Central  PubMed  Article  Google Scholar 

  67. 67.

    Koller A, Bagi Z (2004) Nitric oxide and H2O2 contribute to reactive dilation of isolated coronary arterioles. Am J Physiol Heart Circ Physiol 287:H2461–H2467

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Koller A, Sun D, Messina EJ, Kaley G (1993) l-arginine analogues blunt prostaglandin-related dilation of arterioles. Am J Physiol 264:H1194–H1199

    CAS  PubMed  Google Scholar 

  69. 69.

    Hwa JJ, Ghibaudi L, Williams P, Chatterjee M (1994) Comparison of acetylcholine-dependent relaxation in large and small arteries of rat mesenteric vascular bed. Am J Physiol 266:H952–H958

    CAS  PubMed  Google Scholar 

  70. 70.

    Luksha L, Agewall S, Kublickiene K (2009) Endothelium-derived hyperpolarizing factor in vascular physiology and cardiovascular disease. Atherosclerosis. 202:330–344

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Nishikawa Y, Stepp DW, Chilian WM (1999) In vivo location and mechanism of EDHF-mediated vasodilation in canine coronary microcirculation. Am J Physiol 277:H1252–H1259

    CAS  PubMed  Google Scholar 

  72. 72.

    Shimokawa H, Yasutake H, Fujii K, Owada MK, Nakaike R, Fukumoto Y, Takayanagi T, Nagao T, Egashira K, Fujishima M, Takeshita A (1996) The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation. J Cardiovasc Pharmacol 28:703–711

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Nagao T, Illiano S, Vanhoutte PM (1992) Heterogeneous distribution of endothelium-dependent relaxations resistant to NG-nitro-l-arginine in rats. Am J Physiol 263:H1090–H1094

    CAS  PubMed  Google Scholar 

  74. 74.

    Cohen RA, Plane F, Najibi S, Huk I, Malinski T, Garland CJ (1997) Nitric oxide is the mediator of both endothelium-dependent relaxation and hyperpolarization of the rabbit carotid artery. Proc Natl Acad Sci USA 94:4193–4198

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  75. 75.

    Chataigneau T, Feletou M, Huang PL, Fishman MC, Duhault J, Vanhoutte PM (1999) Acetylcholine-induced relaxation in blood vessels from endothelial nitric oxide synthase knockout mice. Br J Pharmacol 126:219–226

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  76. 76.

    Garland CJ, Plane F, Kemp BK, Cocks TM (1995) Endothelium-dependent hyperpolarization: a role in the control of vascular tone. Trends Pharmacol Sci 16:23–30

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Guillot PV, Guan J, Liu L, Kuivenhoven JA, Rosenberg RD, Sessa WC, Aird WC (1999) A vascular bed-specific pathway. J Clin Investig 103:799–805

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  78. 78.

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

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  79. 79.

    Qian J, Fulton D (2013) Post-translational regulation of endothelial nitric oxide synthase in vascular endothelium. Front Physiol 4:347

    PubMed Central  PubMed  Article  Google Scholar 

  80. 80.

    Michel T, Li GK, Busconi L (1993) Phosphorylation and subcellular translocation of endothelial nitric oxide synthase. Proc Natl Acad Sci USA 90:6252–6256

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  81. 81.

    Lam CF, Peterson TE, Richardson DM, Croatt AJ, d’Uscio LV, Nath KA, Katusic ZS (2006) Increased blood flow causes coordinated upregulation of arterial eNOS and biosynthesis of tetrahydrobiopterin. Am J Physiol Heart Circ Physiol 290:H786–H793

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH (2007) Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol 49:2379–2393

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Lu D, Kassab GS (2011) Role of shear stress and stretch in vascular mechanobiology. J R Soc Interface R Soc 8:1379–1385

    CAS  Article  Google Scholar 

  84. 84.

    Reneman RS, Hoeks AP (2008) Wall shear stress as measured in vivo: consequences for the design of the arterial system. Med Biol Eng Compu 46:499–507

    Article  Google Scholar 

  85. 85.

    Reneman RS, Arts T, Hoeks AP (2006) Wall shear stress—an important determinant of endothelial cell function and structure—in the arterial system in vivo. Discrepancies with theory. J Vasc Res 43:251–269

    PubMed  Article  Google Scholar 

  86. 86.

    Cheng C, van Haperen R, de Waard M, van Damme LC, Tempel D, Hanemaaijer L, van Cappellen GW, Bos J, Slager CJ, Duncker DJ, van der Steen AF, de Crom R, Krams R (2005) Shear stress affects the intracellular distribution of eNOS: direct demonstration by a novel in vivo technique. Blood 106:3691–3698

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Dancu MB, Tarbell JM (2007) Coronary endothelium expresses a pathologic gene pattern compared to aortic endothelium: correlation of asynchronous hemodynamics and pathology in vivo. Atherosclerosis 192:9–14

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Guo X, Kassab GS (2009) Role of shear stress on nitrite and NOS protein content in different size conduit arteries of swine. Acta Physiol 197:99–106

    CAS  Article  Google Scholar 

  89. 89.

    Laughlin MH, Turk JR, Schrage WG, Woodman CR, Price EM (2003) Influence of coronary artery diameter on eNOS protein content. Am J Physiol Heart Circ Physiol 284:H1307–H1312

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Sanchez FA, Savalia NB, Duran RG, Lal BK, Boric MP, Duran WN (2006) Functional significance of differential eNOS translocation. Am J Physiol Heart Circ Physiol 291:H1058–H1064

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  91. 91.

    Iwakiri Y, Satoh A, Chatterjee S, Toomre DK, Chalouni CM, Fulton D, Groszmann RJ, Shah VH, Sessa WC (2006) Nitric oxide synthase generates nitric oxide locally to regulate compartmentalized protein S-nitrosylation and protein trafficking. Proc Natl Acad Sci USA 103:19777–19782

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  92. 92.

    Qian J, Zhang Q, Church JE, Stepp DW, Rudic RD, Fulton DJ (2010) Role of local production of endothelium-derived nitric oxide on cGMP signaling and S-nitrosylation. Am J Physiol Heart Circ Physiol 298:H112–H118

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  93. 93.

    Straub AC, Lohman AW, Billaud M, Johnstone SR, Dwyer ST, Lee MY, Bortz PS, Best AK, Columbus L, Gaston B, Isakson BE (2012) Endothelial cell expression of haemoglobin alpha regulates nitric oxide signalling. Nature 491:473–477

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  94. 94.

    Straub AC, Zeigler AC, Isakson BE (2014) The myoendothelial junction: connections that deliver the message. Physiology 29:242–249

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  95. 95.

    Straub AC, Billaud M, Johnstone SR, Best AK, Yemen S, Dwyer ST, Looft-Wilson R, Lysiak JJ, Gaston B, Palmer L, Isakson BE (2011) Compartmentalized connexin 43 s-nitrosylation/denitrosylation regulates heterocellular communication in the vessel wall. Arterioscler Thromb Vasc Biol 31:399–407

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  96. 96.

    Sandow SL, Hill CE (2000) Incidence of myoendothelial gap junctions in the proximal and distal mesenteric arteries of the rat is suggestive of a role in endothelium-derived hyperpolarizing factor-mediated responses. Circ Res 86:341–346

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Zou MH, Hou XY, Shi CM, Nagata D, Walsh K, Cohen RA (2002) Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase. J Biol Chem 277:32552–32557

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Zou MH, Shi C, Cohen RA (2002) Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest. 109:817–826

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  99. 99.

    Miller AA, Drummond GR, Schmidt HH, Sobey CG (2005) NADPH oxidase activity and function are profoundly greater in cerebral versus systemic arteries. Circ Res 97:1055–1062

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  101. 101.

    Dayal S, Brown KL, Weydert CJ, Oberley LW, Arning E, Bottiglieri T, Faraci FM, Lentz SR (2002) Deficiency of glutathione peroxidase-1 sensitizes hyperhomocysteinemic mice to endothelial dysfunction. Arterioscler Thromb Vasc Biol 22:1996–2002

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Drummond GR, Cai H, Davis ME, Ramasamy S, Harrison DG (2000) Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide. Circ Res 86:347–354

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Wedgwood S, Steinhorn RH, Bunderson M, Wilham J, Lakshminrusimha S, Brennan LA, Black SM (2005) Increased hydrogen peroxide downregulates soluble guanylate cyclase in the lungs of lambs with persistent pulmonary hypertension of the newborn. Am J Physiol Lung Cell Mol Physiol 289:L660–L666

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  104. 104.

    Aschner JL, Foster SL, Kaplowitz M, Zhang Y, Zeng H, Fike CD (2007) Heat shock protein 90 modulates endothelial nitric oxide synthase activity and vascular reactivity in the newborn piglet pulmonary circulation. Am J Physiol Lung Cell Mol Physiol 292:L1515–L1525

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Ushio-Fukai M, Hilenski L, Santanam N, Becker PL, Ma Y, Griendling KK, Alexander RW (2001) Cholesterol depletion inhibits epidermal growth factor receptor transactivation by angiotensin II in vascular smooth muscle cells: role of cholesterol-rich microdomains and focal adhesions in angiotensin II signaling. J Biol Chem 276:48269–48275

    CAS  PubMed  Google Scholar 

  106. 106.

    Salvemini D, de Nucci G, Gryglewski RJ, Vane JR (1989) Human neutrophils and mononuclear cells inhibit platelet aggregation by releasing a nitric oxide-like factor. Proc Natl Acad Sci USA 86:6328–6332

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  107. 107.

    Kubes P, Suzuki M, Granger DN (1991) Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 88:4651–4655

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  108. 108.

    Tomita H, Egashira K, Kubo-Inoue M, Usui M, Koyanagi M, Shimokawa H, Takeya M, Yoshimura T, Takeshita A (1998) Inhibition of NO synthesis induces inflammatory changes and monocyte chemoattractant protein-1 expression in rat hearts and vessels. Arterioscler Thromb Vasc Biol 18:1456–1464

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Zeiher AM, Fisslthaler B, Schray-Utz B, Busse R (1995) Nitric oxide modulates the expression of monocyte chemoattractant protein 1 in cultured human endothelial cells. Circ Res 76:980–986

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Arndt H, Russell JB, Kurose I, Kubes P, Granger DN (1993) Mediators of leukocyte adhesion in rat mesenteric venules elicited by inhibition of nitric oxide synthesis. Gastroenterology 105:675–680

    CAS  PubMed  Google Scholar 

  111. 111.

    Kubes P, Granger DN (1992) Nitric oxide modulates microvascular permeability. Am J Physiol 262:H611–H615

    CAS  PubMed  Google Scholar 

  112. 112.

    Qian H, Neplioueva V, Shetty GA, Channon KM, George SE (1999) Nitric oxide synthase gene therapy rapidly reduces adhesion molecule expression and inflammatory cell infiltration in carotid arteries of cholesterol-fed rabbits. Circulation 99:2979–2982

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Santin JR, Daufenback Machado I, Rodrigues SF, Teixeira S, Muscara MN, Lins Galdino S, da Rocha Pitta I, Farsky SH (2013) Role of an indole-thiazolidine molecule PPAR pan-agonist and COX inhibitor on inflammation and microcirculatory damage in acute gastric lesions. PLoS One 8:e76894

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  114. 114.

    Yamashita T, Sakamoto K, Yamanishi H, Totani N, Yamamoto J (2013) Effect of a free radical scavenger on nitric oxide release in microvessels. Vascul Pharmacol 58:134–139

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Forstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33(829–37):829–837

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  116. 116.

    Li D, Laubach VE, Johns RA (2001) Upregulation of lung soluble guanylate cyclase during chronic hypoxia is prevented by deletion of eNOS. Am J Physiol Lung Cell Mol Physiol 281:L369–L376

    CAS  PubMed  Google Scholar 

  117. 117.

    Guha P, Dey A, Chatterjee A, Chattopadhyay S, Bandyopadhyay SK (2010) Pro-ulcer effects of resveratrol in mice with indomethacin-induced gastric ulcers are reversed by l-arginine. Br J Pharmacol 159:726–734

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  118. 118.

    Drapier JC, Wietzerbin J, Hibbs JB Jr (1988) Interferon-gamma and tumor necrosis factor induce the l-arginine-dependent cytotoxic effector mechanism in murine macrophages. Eur J Immunol 18:1587–1592

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Santin JR, Uchoa FD, Lima Mdo C, Rabello MM, Machado ID, Hernandes MZ, Amato AA, Milton FA, Webb P, Neves Fde A, Galdino SL, Pitta IR, Farsky SH (2013) Chemical synthesis, docking studies and biological effects of a pan peroxisome proliferator-activated receptor agonist and cyclooxygenase inhibitor. Eur J Pharm Sci 48:689–697

    CAS  PubMed  Article  Google Scholar 

  120. 120.

    Del Maestro RF (1982) Role of superoxide anion radicals in microvascular permeability and leukocyte behaviour. Can J Physiol Pharmacol 60:1406–1414

    PubMed  Article  Google Scholar 

  121. 121.

    Kaminski A, Pohl CB, Sponholz C, Ma N, Stamm C, Vollmar B, Steinhoff G (2004) Up-regulation of endothelial nitric oxide synthase inhibits pulmonary leukocyte migration following lung ischemia-reperfusion in mice. Am J Pathol 164:2241–2249

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  122. 122.

    Cai H, Harrison DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87:840–844

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Cardona-Sanclemente LE, Born GV (1995) Effect of inhibition of nitric oxide synthesis on the uptake of LDL and fibrinogen by arterial walls and other organs of the rat. Br J Pharmacol 114:1490–1494

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  124. 124.

    Hossain M, Qadri SM, Liu L (2012) Inhibition of nitric oxide synthesis enhances leukocyte rolling and adhesion in human microvasculature. J Inflamm (Lond) 9:28

    CAS  Article  Google Scholar 

  125. 125.

    Roman A, McGahren ED (2006) l-NAME-induced neutrophil accumulation in rat lung is not entirely because of interactions with l- and P-selectins or CD18. J Pediatr Surg 41:1743–1749

    PubMed  Article  Google Scholar 

  126. 126.

    Carden DL, Young JA, Granger DN (1985) Pulmonary microvascular injury after intestinal ischemia-reperfusion: role of P-selectin. J Appl Physiol 1993(75):2529–2534

    Google Scholar 

  127. 127.

    Lefer DJ, Jones SP, Girod WG, Baines A, Grisham MB, Cockrell AS, Huang PL, Scalia R (1999) Leukocyte-endothelial cell interactions in nitric oxide synthase-deficient mice. Am J Physiol 276:H1943–H1950

    CAS  PubMed  Google Scholar 

  128. 128.

    Sun HX, Zeng DY, Li RT, Pang RP, Yang H, Hu YL, Zhang Q, Jiang Y, Huang LY, Tang YB, Yan GJ, Zhou JG (2012) Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by targeting endothelial nitric oxide synthase. Hypertension 60:1407–1414

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    Chrissobolis S, Faraci FM (2008) The role of oxidative stress and NADPH oxidase in cerebrovascular disease. Trends Mol Med 14:495–502

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  130. 130.

    Chrissobolis S, Miller AA, Drummond GR, Kemp-Harper BK, Sobey CG (2011) Oxidative stress and endothelial dysfunction in cerebrovascular disease. Front Biosci (Landmark Ed) 16:1733–1745

    CAS  Article  Google Scholar 

  131. 131.

    Touyz RM (2004) Reactive oxygen species and angiotensin II signaling in vascular cells—implications in cardiovascular disease. Braz J Med Biol Res 37:1263–1273

    CAS  PubMed  Article  Google Scholar 

  132. 132.

    Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N, Masters BS, Karoui H, Tordo P, Pritchard KA Jr (1998) Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA 95:9220–9225

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  133. 133.

    Aird WC (2003) The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101:3765–3777

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Giusti-Paiva A, Martinez MR, Felix JV, da Rocha MJ, Carnio EC, Elias LL, Antunes-Rodrigues J (2004) Simvastatin decreases nitric oxide overproduction and reverts the impaired vascular responsiveness induced by endotoxic shock in rats. Shock. 21:271–275

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    Ermert M, Ruppert C, Gunther A, Duncker HR, Seeger W, Ermert L (2002) Cell-specific nitric oxide synthase-isoenzyme expression and regulation in response to endotoxin in intact rat lungs. Lab Invest 82:425–441

    CAS  PubMed  Article  Google Scholar 

  136. 136.

    Liu SF, Newton R, Evans TW, Barnes PJ (1996) Differential regulation of cyclo-oxygenase-1 and cyclo-oxygenase-2 gene expression by lipopolysaccharide treatment in vivo in the rat. Clin Sci (Lond). 90:301–306

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Scott JA, Mehta S, Duggan M, Bihari A, McCormack DG (2002) Functional inhibition of constitutive nitric oxide synthase in a rat model of sepsis. Am J Respir Crit Care Med 165:1426–1432

    PubMed  Article  Google Scholar 

  138. 138.

    McGown CC, Brown NJ, Hellewell PG, Reilly CS, Brookes ZL (2010) Beneficial microvascular and anti-inflammatory effects of pravastatin during sepsis involve nitric oxide synthase III. Br J Anaesth 104:183–190

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    Kamoun WS, Karaa A, Kresge N, Merkel SM, Korneszczuk K, Clemens MG (2006) LPS inhibits endothelin-1-induced endothelial NOS activation in hepatic sinusoidal cells through a negative feedback involving caveolin-1. Hepatology 43:182–190

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    La Mura V, Pasarin M, Meireles CZ, Miquel R, Rodriguez-Vilarrupla A, Hide D, Gracia-Sancho J, Garcia-Pagan JC, Bosch J, Abraldes JG (2013) Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction. Hepatology 57:1172–1181

    PubMed  Article  CAS  Google Scholar 

  141. 141.

    Singer G, Stokes KY, Neil Granger D (2013) Reactive oxygen and nitrogen species in sepsis-induced hepatic microvascular dysfunction. Inflamm Res 62:155–164

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  142. 142.

    Yamashita T, Kawashima S, Ohashi Y, Ozaki M, Ueyama T, Ishida T, Inoue N, Hirata K, Akita H, Yokoyama M (2000) Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthase. Circulation 101:931–937

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Cobb JP, Natanson C, Hoffman WD, Lodato RF, Banks S, Koev CA, Solomon MA, Elin RJ, Hosseini JM, Danner RL (1992) N omega-amino-l-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin. J Exp Med 176:1175–1182

    CAS  PubMed  Article  Google Scholar 

  144. 144.

    Cerwinka WH, Cooper D, Krieglstein CF, Ross CR, McCord JM, Granger DN (2003) Superoxide mediates endotoxin-induced platelet-endothelial cell adhesion in intestinal venules. Am J Physiol Heart Circ Physiol 284:H535–H541

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Murrell W (1879) Nitro-Glycerine in angina pectoris. Lancet 1:80–81

    Article  Google Scholar 

  146. 146.

    Golwala NH, Hodenette C, Murthy SN, Nossaman BD, Kadowitz PJ (2009) Vascular responses to nitrite are mediated by xanthine oxidoreductase and mitochondrial aldehyde dehydrogenase in the rat. Can J Physiol Pharmacol 87:1095–1101

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Napoli C, Ignarro LJ (2003) Nitric oxide-releasing drugs. Annu Rev Pharmacol Toxicol 43:97–123

    CAS  PubMed  Article  Google Scholar 

  148. 148.

    Robin ED, McCauley R (1992) Nitroprusside-related cyanide poisoning. Time (long past due) for urgent, effective interventions. Chest 102:1842–1845

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Klatt P, Pfeiffer S, List BM, Lehner D, Glatter O, Bachinger HP, Werner ER, Schmidt K, Mayer B (1996) Characterization of heme-deficient neuronal nitric-oxide synthase reveals a role for heme in subunit dimerization and binding of the amino acid substrate and tetrahydrobiopterin. J Biol Chem 271:7336–7342

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Rees DD, Palmer RMJ, Schulz R, Hodson HF, Moncada S (1990) Characterization of 3 inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol 101:746–752

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  151. 151.

    RodriguezCrespo I, Gerber NC, deMontellano PRO (1996) Endothelial nitric-oxide synthase—expression in Escherichia coli, spectroscopic characterization, and role of tetrahydrobiopterin in dimer formation. J Biol Chem 271:11462–11467

    CAS  Article  Google Scholar 

  152. 152.

    Pant K, Crane BR (2005) Structure of a loose dimer: an intermediate in nitric oxide synthase assembly. J Mol Biol 352:932–940

    CAS  PubMed  Article  Google Scholar 

  153. 153.

    Sennequier N, Wolan D, Stuehr DJ (1999) Antifungal imidazoles block assembly of inducible NO synthase into an active dimer. J Biol Chem 274:930–938

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Paige JS, Jaffrey SR (2007) Pharmacologic manipulation of nitric oxide signaling: targeting NOS dimerization and protein–protein interactions. Curr Top Med Chem 7:97–114

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Broccard A, Hurni JM, Eckert P, Liaudet L, Schaller MD, Lazor R, Perret C, Feihl F (2000) Tissue oxygenation and hemodynamic response to NO synthase inhibition in septic shock. Shock 14:35–40

    CAS  PubMed  Article  Google Scholar 

  156. 156.

    Avontuur JA, Tutein Nolthenius RP, van Bodegom JW, Bruining HA (1998) Prolonged inhibition of nitric oxide synthesis in severe septic shock: a clinical study. Crit Care Med 26:660–667

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Bernatchez PN, Bauer PM, Yu J, Prendergast JS, He P, Sessa WC (2005) Dissecting the molecular control of endothelial NO synthase by caveolin-1 using cell-permeable peptides. Proc Natl Acad Sci USA 102:761–766

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  158. 158.

    Bucci M, Gratton J-P, Rudic RD, Acevedo L, Roviezzo F, Cirino G, Sessa WC (2000) In vivo deliveryof the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation. Nat Med 6:1362–1367

    CAS  PubMed  Article  Google Scholar 

  159. 159.

    Sellers SL, Trane AE, Bernatchez PN (2012) Caveolin as a potential drug target for cardiovascular protection. Front Physiol 3:280

    PubMed Central  PubMed  Article  Google Scholar 

  160. 160.

    Trane AE, Pavlov D, Sharma A, Saqib U, Lau K, van Petegem F, Minshall RD, Roman LJ, Bernatchez PN (2014) Deciphering the binding of caveolin-1 to client protein endothelial nitric-oxide synthase (eNOS): scaffolding subdomain identification, interaction modeling, and biological significance. J Biol Chem 289:13273–13283

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  161. 161.

    Bernatchez P, Sharma A, Bauer PM, Marin E, Sessa WC (2011) A noninhibitory mutant of the caveolin-1 scaffolding domain enhances eNOS-derived NO synthesis and vasodilation in mice. J Clin Investig 121:3747–3755

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  162. 162.

    Liu X, Miller MJ, Joshi MS, Sadowska-Krowicka H, Clark DA, Lancaster JR Jr (1998) Diffusion-limited reaction of free nitric oxide with erythrocytes. J Biol Chem 273:18709–18713

    CAS  PubMed  Article  Google Scholar 

  163. 163.

    Butler AR, Megson IL, Wright PG (1998) Diffusion of nitric oxide and scavenging by blood in the vasculature. Biochimica et Biophysica Acta (BBA) General Subjects 1425:168–176

    CAS  Article  Google Scholar 

  164. 164.

    Liao JC, Hein TW, Vaughn MW, Huang K-T, Kuo L (1999) Intravascular flow decreases erythrocyte consumption of nitric oxide. PNAS 96:8757–8761

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  165. 165.

    Azarov I, Huang KT, Basu S, Gladwin MT, Hogg N, Kim-Shapiro DB (2005) Nitric oxide scavenging by red blood cells as a function of hematocrit and oxygenation. J Biol Chem United States 280:39024–39032

    CAS  Article  Google Scholar 

  166. 166.

    Kleinbongard P, Schulz R, Rassaf T, Lauer T, Dejam A, Jax T, Kumara I, Gharini P, Kabanova S, Ozuyaman B, Schnurch HG, Godecke A, Weber AA, Robenek M, Robenek H, Bloch W, Rosen P, Kelm M (2006) Red blood cells express a functional endothelial nitric oxide synthase. Blood United States 107:2943–2951

    CAS  Google Scholar 

  167. 167.

    Vaughn MW, Huang KT, Kuo L, Liao JC (2000) Erythrocytes possess an intrinsic barrier to nitric oxide consumption. J Biol Chem 275:2342–2348

    CAS  PubMed  Article  Google Scholar 

  168. 168.

    Helms C, Kim-Shapiro DB (2013) Hemoglobin-mediated nitric oxide signaling. Free Radic Biol Med 61:464–472

    CAS  PubMed  Article  Google Scholar 

  169. 169.

    Jubelin BC, Gierman JL (1996) Erythrocytes may synthesize their own nitric oxide. Am J Hypertens United States 9:1214–1219

    CAS  Article  Google Scholar 

  170. 170.

    Kang ES, Ford K, Grokulsky G, Wang YB, Chiang TM, Acchiardo SR (2000) Normal circulating adult human red blood cells contain inactive NOS proteins. J Lab Clin Med United States 135:444–451

    CAS  Article  Google Scholar 

  171. 171.

    Cortese-Krott MM, Rodriguez-Mateos A, Sansone R, Kuhnle GG, Thasian-Sivarajah S, Krenz T, Horn P, Krisp C, Wolters D, Heiss C, Kroncke KD, Hogg N, Feelisch M, Kelm M (2012) Human red blood cells at work: identification and visualization of erythrocytic eNOS activity in health and disease. Blood United States 120:4229–4237

    CAS  Google Scholar 

  172. 172.

    Wood KC, Cortese-Krott MM, Kovacic JC, Noguchi A, Liu VB, Wang X, Raghavachari N, Boehm M, Kato GJ, Kelm M, Gladwin MT (2013) Circulating blood endothelial nitric oxide synthase contributes to the regulation of systemic blood pressure and nitrite homeostasis. Arterioscler Thromb Vasc Biol 33:1861–1871

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    Ulker P, Sati L, Celik-Ozenci C, Meiselman HJ, Baskurt OK (2009) Mechanical stimulation of nitric oxide synthesizing mechanisms in erythrocytes. Biorheology 46:121–132

    CAS  PubMed  Google Scholar 

  174. 174.

    Bor-Kucukatay M, Wenby RB, Meiselman HJ, Baskurt OK (2003) Effects of nitric oxide on red blood cell deformability. Am J Physiol Heart Circ Physiol United States 284:H1577–H1584

    CAS  Article  Google Scholar 

  175. 175.

    Cortese-Krott MM, Kelm M (2014) Endothelial nitric oxide synthase in red blood cells: key to a new erythrocrine function? Redox Biol 2:251–258

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  176. 176.

    Garcia-Cardena G, Fan R, Stern DF, Liu J, Sessa WC (1996) Endothelial nitric oxide synthase is regulated by tyrosine phosphorylation and interacts with caveolin-1. J Biol Chem 271:27237–27240

    CAS  PubMed  Article  Google Scholar 

  177. 177.

    Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC (1999) Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399:597–601

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  178. 178.

    Bauer PM, Fulton D, Boo YC, Sorescu GP, Kemp BE, Jo H, Sessa WC (2003) Compensatory phosphorylation and protein–protein interactions revealed by loss of function and gain of function mutants of multiple serine phosphorylation sites in endothelial nitric-oxide synthase. J Biol Chem 278:14841–14849

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgments

This work was supported by National Institutes of Health Grants HL088554 (BEI), HL107963 (BEI). The American Heart Association provided predoctoral (LAB) and postdoctoral (JTB) fellowships that supported this work. JTB was supported by a National Institutes of Health training Grant (HL007284). Support was also provided by the National Natural Science Foundation of China (XS; 81072063) and China Scholarship Council (XS; 201408210085).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Brant E. Isakson.

Additional information

X. Shu and T. C. Stevenson Keller IV contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shu, X., Keller, T.C.S., Begandt, D. et al. Endothelial nitric oxide synthase in the microcirculation. Cell. Mol. Life Sci. 72, 4561–4575 (2015). https://doi.org/10.1007/s00018-015-2021-0

Download citation

Keywords

  • Endothelial nitric oxide synthase
  • Nitric oxide
  • Endothelium
  • Microcirculation