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Gene Review

Nos3  -  nitric oxide synthase 3, endothelial cell

Rattus norvegicus

Synonyms: Constitutive NOS, EC-NOS, Endothelial NOS, NOS type III, NOSIII, ...
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Disease relevance of Nos3


Psychiatry related information on Nos3

  • Impaired endothelial nitric oxide synthase (eNOS) function is associated with erectile dysfunction in diabetes mellitus, but the exact molecular basis for the eNOS defect in the diabetic penis remains unclear [5].
  • Therefore, the authors' first goal was to determine whether long-term alcohol consumption alters eNOS-dependent and nNOS-dependent reactivity of pial arterioles in female rats [6].
  • Thus for the first time we showed that mesenteric eNOS overexpression could explain at least partly why chronic estrogen treatment suppressed the enhanced cardiovascular responses to psychological stress in the ovariectomized rat [7].

High impact information on Nos3

  • Here we show that the serine/threonine protein kinase Akt (protein kinase B) can directly phosphorylate eNOS on serine 1179 and activate the enzyme, leading to NO production, whereas mutant eNOS (S1179A) is resistant to phosphorylation and activation by Akt [8].
  • Thus, eNOS is a newly described Akt substrate linking signal transduction by Akt to the release of the gaseous second messenger NO [8].
  • We found decreased free nitric oxide (NO) levels in aged rat aortas, in conjunction with a sevenfold higher expression and activity of endothelial NO synthase (eNOS) [9].
  • Endothelial NO synthase (eNOS), but not the inducible isoform (iNOS), was present in mesenteric vasculature of cirrhotic rats with and without BT, and its expression was enhanced compared with controls [10].
  • This TNF-alpha production was associated with elevated levels of tetrahydrobiopterin (BH(4)), a TNF-alpha-stimulated cofactor and enhancer of eNOS-derived NO biosynthesis and NOS activity in mesenteric vasculature [10].

Chemical compound and disease context of Nos3


Biological context of Nos3

  • METHODS: Proinflammatory cytokine levels, Akt and NOS activities, eNOS phosphorylation, and NOS expressions were assessed in aorta from norfloxacin-treated and untreated cirrhotic rats [15].
  • Reduction in eNOS expression together with the concomitant decline in intracellular cyclic GMP levels appears to account for a significant portion of the p38 MAPK-dependent osmotic stimulation of NPR-A gene expression noted previously [16].
  • This study describes a hitherto unrecognized molecular mechanism by which nuclear eNOS through ensuing NO modulates nuclear calcium homeostasis involved in gene transcription-associated events [17].
  • The iNOS signal in callus cells declined to an undetectable level on day 14. eNOS was detected during the middle stages (on day 7 and day 14) of fracture healing in cells lining the blood vessels and also in 49 +/- 3% of cells in the chondral region [18].
  • In LV tissue of SHR at 18 weeks, caveolin-1 and -3 were similarly decreased, but Hsp90 upregulated, together with a downregulation of eNOS [19].

Anatomical context of Nos3

  • In the aging aortas, the expression of both eNOS and iNOS isoforms was enhanced [20].
  • Effects of ET-1 on intralobar pulmonary vascular segment reactivity and on eNOS expression and activity in rat pulmonary microvascular endothelial cells (RPMVECs) were also evaluated [21].
  • CBDL pulmonary artery segments had markedly increased ET(B) receptor mediated, nitric oxide dependent vasodilatory responses to ET-1 compared with controls and ET-1 triggered an ET(B) receptor dependent stimulation of eNOS in RPMVECs [21].
  • Immunohistochemical analysis revealed that eNOS is located in astrocytes of both gray and white matters as well as in blood vessels [22].
  • Induction of eNOS in response to a low dose of LPS, together with its localization in major components of the blood-brain barrier, suggests that brain eNOS is involved in early pathophysiologic response against systemic infection before iNOS is induced with progression of the infection [22].

Associations of Nos3 with chemical compounds


Physical interactions of Nos3

  • However, eNOS was tightly coupled with caveolin-1, and was dissociated from heat shock protein 90 or calmodulin in the hypoxic pulmonary artery in either the presence or absence of carbachol [12].
  • Here we show that cNOS isoforms contain a unique polypeptide insert in their FMN binding domains which is not shared with iNOS or other related flavoproteins [26].
  • Nitric oxide synthases (NOSs) are classified functionally, based on whether calmodulin binding is Ca2+-dependent (cNOS) or Ca2+-independent (iNOS) [26].

Enzymatic interactions of Nos3


Co-localisations of Nos3

  • Morphometric analysis revealed that more than 80% of detectable eNOS was co-localized with caveolin-1 at caveolae under control conditions [28].

Regulatory relationships of Nos3


Other interactions of Nos3


Analytical, diagnostic and therapeutic context of Nos3

  • Furthermore, the expression of the NOS isoforms by Western blot and the eNOS and iNOS activities, defined as Ca2+-dependent and Ca2+-independent conversion of [14C]L-arginine into [14C]L-citrulline, respectively, were also determined [20].
  • Endothelial NOS (ecNOS) mRNA was also detected by RT-PCR in whole bone, and immunohistochemical studies showed widespread ecNOS expression in bone marrow cells and trabecular lining cells in vivo [35].
  • Additionally, immunohistochemistry revealed that the immunostaining intensity of nNOS, eNOS, and iNOS was clearly enhanced in the medullary thick ascending limb, proximal straight tubule, inner medullary collecting duct, and proximal convoluted tubule in WD rats [36].
  • Short-term intravesical instillation of UPEC enhances detrusor contractions through an eNOS-related pathway, but iNOS-regulated ERK1/2 signaling may be involved in long-term UPEC treatment-induced responses [37].
  • Immunoblotting studies demonstrated increased levels of eNOS in the rat lung at 4, 7 and 14 days and iNOS at 7 and 14 days after bleomycin inhalation [4].


  1. Endothelin-1 activates endothelial cell nitric-oxide synthase via heterotrimeric G-protein betagamma subunit signaling to protein jinase B/Akt. Liu, S., Premont, R.T., Kontos, C.D., Huang, J., Rockey, D.C. J. Biol. Chem. (2003) [Pubmed]
  2. Dual role for nitric oxide in dynorphin spinal neurotoxicity. Hu, W.H., Li, F., Qiang, W.A., Liu, N., Wang, G.Q., Xiao, J., Liu, J.S., Liao, W.H., Jen, M.F. J. Neurotrauma (1999) [Pubmed]
  3. Effects of ET-A receptor blockade on eNOS gene expression in chronic hypoxic rat lungs. Blumberg, F.C., Wolf, K., Arzt, M., Lorenz, C., Riegger, G.A., Pfeifer, M. J. Appl. Physiol. (2003) [Pubmed]
  4. Expression of nitric oxide synthase, aquaporin 1 and aquaporin 5 in rat after bleomycin inhalation. Jang, A.S., Lee, J.U., Choi, I.S., Park, K.O., Lee, J.H., Park, S.W., Park, C.S. Intensive care medicine. (2004) [Pubmed]
  5. Inactivation of phosphorylated endothelial nitric oxide synthase (Ser-1177) by O-GlcNAc in diabetes-associated erectile dysfunction. Musicki, B., Kramer, M.F., Becker, R.E., Burnett, A.L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. Sex difference in nitric oxide synthase-dependent dilatation of cerebral arterioles during long-term alcohol consumption. Sun, H., Mayhan, W.G. Alcohol. Clin. Exp. Res. (2005) [Pubmed]
  7. Estrogen replacement suppresses stress-induced cardiovascular responses in ovariectomized rats. Morimoto, K., Kurahashi, Y., Shintani-Ishida, K., Kawamura, N., Miyashita, M., Uji, M., Tan, N., Yoshida, K. Am. J. Physiol. Heart Circ. Physiol. (2004) [Pubmed]
  8. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Fulton, D., Gratton, J.P., McCabe, T.J., Fontana, J., Fujio, Y., Walsh, K., Franke, T.F., Papapetropoulos, A., Sessa, W.C. Nature (1999) [Pubmed]
  9. Enhanced peroxynitrite formation is associated with vascular aging. van der Loo, B., Labugger, R., Skepper, J.N., Bachschmid, M., Kilo, J., Powell, J.M., Palacios-Callender, M., Erusalimsky, J.D., Quaschning, T., Malinski, T., Gygi, D., Ullrich, V., Lüscher, T.F. J. Exp. Med. (2000) [Pubmed]
  10. Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility. Wiest, R., Das, S., Cadelina, G., Garcia-Tsao, G., Milstien, S., Groszmann, R.J. J. Clin. Invest. (1999) [Pubmed]
  11. Beneficial effects of tetramethylpyrazine, an active constituent of Chinese herbs, on rats with endotoxemia. Liao, M.H., Wu, C.C., Yen, M.H. Proc. Natl. Sci. Counc. Repub. China B (1998) [Pubmed]
  12. Decreased endothelial nitric-oxide synthase (eNOS) activity resulting from abnormal interaction between eNOS and its regulatory proteins in hypoxia-induced pulmonary hypertension. Murata, T., Sato, K., Hori, M., Ozaki, H., Karaki, H. J. Biol. Chem. (2002) [Pubmed]
  13. Expression of iNOS, eNOS, and peroxynitrite-modified proteins in experimental anti-myeloperoxidase associated crescentic glomerulonephritis. Heeringa, P., van Goor, H., Moshage, H., Klok, P.A., Huitema, M.G., de Jager, A., Schep, A.J., Kallenberg, C.G. Kidney Int. (1998) [Pubmed]
  14. Nitric oxide synthase and NAD(P)H oxidase modulate coronary endothelial cell growth. Bayraktutan, U. J. Mol. Cell. Cardiol. (2004) [Pubmed]
  15. Norfloxacin reduces aortic NO synthases and proinflammatory cytokine up-regulation in cirrhotic rats: role of Akt signaling. Tazi, K.A., Moreau, R., Hervé, P., Dauvergne, A., Cazals-Hatem, D., Bert, F., Poirel, O., Rabiller, A., Lebrec, D. Gastroenterology (2005) [Pubmed]
  16. Osmoregulation of endothelial nitric-oxide synthase gene expression in inner medullary collecting duct cells. Role in activation of the type A natriuretic peptide receptor. Chen, S., Cao, L., Intengan, H.D., Humphreys, M., Gardner, D.G. J. Biol. Chem. (2002) [Pubmed]
  17. Nitric oxide signaling via nuclearized endothelial nitric-oxide synthase modulates expression of the immediate early genes iNOS and mPGES-1. Gobeil, F., Zhu, T., Brault, S., Geha, A., Vazquez-Tello, A., Fortier, A., Barbaz, D., Checchin, D., Hou, X., Nader, M., Bkaily, G., Gratton, J.P., Heveker, N., Ribeiro-da-Silva, A., Peri, K., Bard, H., Chorvatova, A., D'Orléans-Juste, P., Goetzl, E.J., Chemtob, S. J. Biol. Chem. (2006) [Pubmed]
  18. Localization of nitric oxide synthases during fracture healing. Zhu, W., Murrell, G.A., Lin, J., Gardiner, E.M., Diwan, A.D. J. Bone Miner. Res. (2002) [Pubmed]
  19. Differential regulation of nitric oxide synthases and their allosteric regulators in heart and vessels of hypertensive rats. Piech, A., Dessy, C., Havaux, X., Feron, O., Balligand, J.L. Cardiovasc. Res. (2003) [Pubmed]
  20. Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats. Cernadas, M.R., Sánchez de Miguel, L., García-Durán, M., González-Fernández, F., Millás, I., Montón, M., Rodrigo, J., Rico, L., Fernández, P., de Frutos, T., Rodríguez-Feo, J.A., Guerra, J., Caramelo, C., Casado, S., López-Farré, n.u.l.l. Circ. Res. (1998) [Pubmed]
  21. The role of endothelin-1 and the endothelin B receptor in the pathogenesis of hepatopulmonary syndrome in the rat. Ling, Y., Zhang, J., Luo, B., Song, D., Liu, L., Tang, L., Stockard, C.R., Grizzle, W.E., Ku, D.D., Fallon, M.B. Hepatology (2004) [Pubmed]
  22. Induction of endothelial nitric-oxide synthase in rat brain astrocytes by systemic lipopolysaccharide treatment. Iwase, K., Miyanaka, K., Shimizu, A., Nagasaki, A., Gotoh, T., Mori, M., Takiguchi, M. J. Biol. Chem. (2000) [Pubmed]
  23. Decreased renal expression of nitric oxide synthase isoforms in adrenocorticotropin-induced and corticosterone-induced hypertension. Lou , Y.K., Wen, C., Li, M., Adams, D.J., Wang , M.X., Yang, F., Morris, B.J., Whitworth, J.A. Hypertension (2001) [Pubmed]
  24. Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. Schwartz, D., Mendonca, M., Schwartz, I., Xia, Y., Satriano, J., Wilson, C.B., Blantz, R.C. J. Clin. Invest. (1997) [Pubmed]
  25. LPS inhibits endothelin-1-induced endothelial NOS activation in hepatic sinusoidal cells through a negative feedback involving caveolin-1. Kamoun, W.S., Karaa, A., Kresge, N., Merkel, S.M., Korneszczuk, K., Clemens, M.G. Hepatology (2006) [Pubmed]
  26. An autoinhibitory control element defines calcium-regulated isoforms of nitric oxide synthase. Salerno, J.C., Harris, D.E., Irizarry, K., Patel, B., Morales, A.J., Smith, S.M., Martasek, P., Roman, L.J., Masters, B.S., Jones, C.L., Weissman, B.A., Lane, P., Liu, Q., Gross, S.S. J. Biol. Chem. (1997) [Pubmed]
  27. Time-dependent inhibition and tetrahydrobiopterin depletion of endothelial nitric-oxide synthase caused by cigarettes. Lowe, E.R., Everett, A.C., Lee, A.J., Lau, M., Dunbar, A.Y., Berka, V., Tsai, A.L., Osawa, Y. Drug Metab. Dispos. (2005) [Pubmed]
  28. Functional interaction of caveolin-1 and eNOS in myocardial capillary endothelium revealed by immunoelectron microscopy. Reiner, M., Bloch, W., Addicks, K. J. Histochem. Cytochem. (2001) [Pubmed]
  29. Role of nitric oxide in traumatic brain injury in the rat. Wada, K., Chatzipanteli, K., Busto, R., Dietrich, W.D. J. Neurosurg. (1998) [Pubmed]
  30. Luminal flow induces eNOS activation and translocation in the rat thick ascending limb. II. Role of PI3-kinase and Hsp90. Ortiz, P.A., Hong, N.J., Garvin, J.L. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  31. Stimulatory effect of IGF-I and VEGF on eNOS message, protein expression, eNOS phosphorylation and nitric oxide production in rat glomeruli, and the involvement of PI3-K signaling pathway. Wang, Y., Nagase, S., Koyama, A. Nitric Oxide (2004) [Pubmed]
  32. Mechanism of impaired nitric oxide synthase activity in skeletal muscle of streptozotocin-induced diabetic rats. Perreault, M., Dombrowski, L., Marette, A. Diabetologia (2000) [Pubmed]
  33. Regional variations and age-related changes in nitric oxide synthase and arginase in the sub-regions of the hippocampus. Liu, P., Smith, P.F., Appleton, I., Darlington, C.L., Bilkey, D.K. Neuroscience (2003) [Pubmed]
  34. TGF-beta(1) modulates NOS expression and phosphorylation of Akt/PKB in rat myocytes exposed to hypoxia-reoxygenation. Chen, H., Li, D., Saldeen, T., Mehta, J.L. Am. J. Physiol. Heart Circ. Physiol. (2001) [Pubmed]
  35. Expression of nitric oxide synthase isoforms in bone and bone cell cultures. Helfrich, M.H., Evans, D.E., Grabowski, P.S., Pollock, J.S., Ohshima, H., Ralston, S.H. J. Bone Miner. Res. (1997) [Pubmed]
  36. Increased nitric oxide synthase mRNA expression in the renal medulla of water-deprived rats. Shin, S.J., Lai, F.J., Wen, J.D., Lin, S.R., Hsieh, M.C., Hsiao, P.J., Tsai, J.H. Kidney Int. (1999) [Pubmed]
  37. Uropathogenic Escherichia coli Alters Muscle Contractions in Rat Urinary Bladder via a Nitric Oxide Synthase-Related Signaling Pathway. Weng, T.I., Chen, W.J., Wu, H.Y., Liu, S.H. J. Infect. Dis. (2006) [Pubmed]
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