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Gene Review

NOS3  -  nitric oxide synthase 3 (endothelial cell)

Ovis aries

Synonyms: EC-NOS, NOSIII, cNOS, eNOS
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Disease relevance of eNOS


High impact information on eNOS

  • In studies of intact ovine endothelial cells, 17beta-estradiol (E2) caused acute (five-minute) activation of eNOS that was unaffected by actinomycin D but was fully inhibited by concomitant acute treatment with specific estrogen receptor (ER) antagonists [4].
  • These findings demonstrate that the short-term effects of estrogen central to cardiovascular physiology are mediated by ERalpha functioning in a novel, nongenomic manner to activate eNOS via MAP kinase-dependent mechanisms [4].
  • In addition, the acute response of eNOS to E2 was reconstituted in COS-7 cells cotransfected with wild-type ERalpha and eNOS, but not by transfection with eNOS alone [4].
  • Furthermore, the inhibition of tyrosine kinases or mitogen-activated protein (MAP) kinase kinase prevented the activation of eNOS by E2, and E2 caused rapid ER-dependent activation of MAP kinase [4].
  • Estrogen is an important vasoprotective molecule that causes the rapid dilation of blood vessels by activating endothelial nitric oxide synthase (eNOS) through an unknown mechanism [4].

Chemical compound and disease context of eNOS

  • However, endothelial nitric oxide synthase protein expression was similar in both groups, whereas endothelium-independent relaxation to sodium nitroprusside was greater in the fistula group compared with controls [5].

Biological context of eNOS

  • We investigated signaling mechanisms underlying pulsatile shear stress-induced increases in eNOS phosphorylation and protein expression by OFPAE cells [6].
  • The ovine eNOS cDNA has high homology to published human and bovine sequences and shares identity with the bovine amino acid sequence [7].
  • To determine the effects of intrauterine hypertension on lung eNOS content, fetal lung tissue was harvested 8-12 days after intrauterine closure of the ductus arteriosus (DA) performed at 125-128 days of gestation (term = 147 days) [1].
  • Thus, acylation targets eNOS to plasmalemmal caveolae [8].
  • We designed studies to determine whether eNOS is localized to plasmalemmal microdomains implicated in signal transduction called caveolae [8].

Anatomical context of eNOS

  • The sheep, however, is widely used as a model for cardiovascular adaptation to pregnancy and ovine uterine artery endothelial cell (UAEC) eNOS undergoes pregnancy-specific (P) enhancement of activity associated with increased Ca(2+) and protein kinase signaling in response to a number of agonists, including adenosine triphosphate (ATP) [7].
  • When ovine eNOS was transiently expressed in COS-7 cells (COS-7/oeNOS), A23187 increased specific catalytic activity in a dose- and time-dependent manner [7].
  • Although positive immunostaining for eNOS persisted in lung vascular endothelium, eNOS protein content was reduced by 48%, as measured by Western analysis (P < 0.001) [1].
  • Immunoelectron microscopy showed that eNOS heavily decorated endothelial caveolae, whereas coated pits and smooth plasma membrane were devoid of gold particles [8].
  • In newborn lambs, PTHrP-induced relaxation was not affected by endothelium removal, inhibition of eNOS, or inhibition of adenylyl cyclases by SQ-22536 [9].

Associations of eNOS with chemical compounds


Regulatory relationships of eNOS

  • We evaluated eNOS activation by E2 in cultured endothelial cells that express endogenous ERbeta to determine whether the ERbeta isoform has nongenomic action and to reveal the subcellular locale of that function [12].

Other interactions of eNOS


Analytical, diagnostic and therapeutic context of eNOS


  1. Chronic intrauterine pulmonary hypertension impairs endothelial nitric oxide synthase in the ovine fetus. Villamor, E., Le Cras, T.D., Horan, M.P., Halbower, A.C., Tuder, R.M., Abman, S.H. Am. J. Physiol. (1997) [Pubmed]
  2. Effect of chronic hypoxemia on the regulation of nitric-oxide synthase in the fetal sheep brain. Aguan, K., Murotsuki, J., Gagnon, R., Thompson, L.P., Weiner, C.P. Brain Res. Dev. Brain Res. (1998) [Pubmed]
  3. Upregulation of eNOS in pregnant ovine uterine arteries by chronic hypoxia. Xiao, D., Bird, I.M., Magness, R.R., Longo, L.D., Zhang, L. Am. J. Physiol. Heart Circ. Physiol. (2001) [Pubmed]
  4. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. Chen, Z., Yuhanna, I.S., Galcheva-Gargova, Z., Karas, R.H., Mendelsohn, M.E., Shaul, P.W. J. Clin. Invest. (1999) [Pubmed]
  5. Systemic arteriovenous fistula leads to pulmonary artery remodeling and abnormal vasoreactivity in the fetal lamb. Jouannic, J.M., Roussin, R., Hislop, A.A., Lanone, S., Martinovic, J., Boczkowski, J., Dumez, Y., Dinh-Xuan, A.T. Am. J. Physiol. Lung Cell Mol. Physiol. (2003) [Pubmed]
  6. Mechanisms of shear stress-induced endothelial nitric-oxide synthase phosphorylation and expression in ovine fetoplacental artery endothelial cells. Li, Y., Zheng, J., Bird, I.M., Magness, R.R. Biol. Reprod. (2004) [Pubmed]
  7. Molecular cloning of ovine endothelial nitric oxide synthase and expression in COS-7 cells. Cale, J.M., Tsoi, S.C., Toppe, M., Grummer, M.A., Ochiai, M., Magness, R.R., Bird, I.M. J. Soc. Gynecol. Investig. (2005) [Pubmed]
  8. Acylation targets emdothelial nitric-oxide synthase to plasmalemmal caveolae. Shaul, P.W., Smart, E.J., Robinson, L.J., German, Z., Yuhanna, I.S., Ying, Y., Anderson, R.G., Michel, T. J. Biol. Chem. (1996) [Pubmed]
  9. Parathyroid hormone-related protein-mediated responses in pulmonary arteries and veins of newborn lambs. Gao, Y., Raj, J.U. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  10. Endothelium-derived nitric oxide synthase protein expression in ovine placental arteries. Sheppard, C., Shaw, C.E., Li, Y., Bird, I.M., Magness, R.R. Biol. Reprod. (2001) [Pubmed]
  11. Estrogen selectively up-regulates eNOS and nNOS in reproductive arteries by transcriptional mechanisms. Rosenfeld, C.R., Chen, C., Roy, T., Liu, X. J. Soc. Gynecol. Investig. (2003) [Pubmed]
  12. ERbeta has nongenomic action in caveolae. Chambliss, K.L., Yuhanna, I.S., Anderson, R.G., Mendelsohn, M.E., Shaul, P.W. Mol. Endocrinol. (2002) [Pubmed]
  13. Expression of nitric oxide synthase isoforms is reduced in late-gestation ovine fetal brainstem. Wood, C.E., Chen, G.F., Keller-Wood, M. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2005) [Pubmed]
  14. Circulating levels of nitric oxide and vascular endothelial growth factor throughout ovine pregnancy. Vonnahme, K.A., Wilson, M.E., Li, Y., Rupnow, H.L., Phernetton, T.M., Ford, S.P., Magness, R.R. J. Physiol. (Lond.) (2005) [Pubmed]
  15. Endothelial vasodilator production by ovine uterine and systemic arteries: ovarian steroid and pregnancy control of ERalpha and ERbeta levels. Byers, M.J., Zangl, A., Phernetton, T.M., Lopez, G., Chen, D.B., Magness, R.R. J. Physiol. (Lond.) (2005) [Pubmed]
  16. Zonal expression of endothelial nitric oxide synthase in sheep and rhesus adrenal cortex. Peterson, J.K., Moran, F., Conley, A.J., Bird, I.M. Endocrinology (2001) [Pubmed]
  17. Persistent eNOS in lung hypoplasia caused by left pulmonary artery ligation in the ovine fetus. Tajchman, U.W., Tuder, R.M., Horan, M., Parker, T.A., Abman, S.H. Am. J. Physiol. (1997) [Pubmed]
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