Cited by 1,957Nitric Oxide and Endothelin EffectsCardiovascular Health and Disease PreventionEicosanoids and Hypertension Pharmacology

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Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace

Förstermann, Ulrich, Münzel, Thomas·2006·Circulation

DOI 10.1161/circulationaha.105.602532

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Abstract

Nitric oxide (NO·) is an important protective molecule in the vasculature, and endothelial NO· synthase (eNOS) is responsible for most of the vascular NO· produced. A functional eNOS oxidizes its substrate l -arginine to l -citrulline and NO·. This normal function of eNOS requires dimerization of the enzyme, the presence of the substrate l -arginine, and the essential cofactor (6 R )-5,6,7,8-tetrahydro- l -biopterin (BH 4 ), one of the most potent naturally occurring reducing agents. Cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes mellitus, or chronic smoking stimulate the production of reactive oxygen species in the vascular wall. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases represent major sources of this reactive oxygen species and have been found upregulated and activated in animal models of hypertension, diabetes, and sedentary lifestyle and in patients with cardiovascular risk factors. Superoxide (O 2 · − ) reacts avidly with vascular NO· to form peroxynitrite (ONOO − ). The cofactor BH 4 is highly sensitive to oxidation by ONOO − . Diminished levels of BH 4 promote O 2 · − production by eNOS (referred to as eNOS uncoupling). This transformation of eNOS from a protective enzyme to a contributor to oxidative stress has been observed in several in vitro models, in animal models of cardiovascular diseases, and in patients with cardiovascular risk factors. In many cases, supplementation with BH 4 has been shown to correct eNOS dysfunction in animal models and patients. In addition, folic acid and infusions of vitamin C are able to restore eNOS functionality, most probably by enhancing BH 4 levels as well.

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10.1161/res.86.3.347 · DOI
Li H Witte K August M Brausch I Gödtel-Armbrust U Habermeier A Closs EI Oelze M Münzel T Förstermann U. Reversal of eNOS uncoupling and upregulation of eNOS expression lowers blood pressure in hypertensive rats. J Am Coll Cardiol. In press.
10.1161/res.88.2.e14 · DOI
10.1161/circ.99.15.2027 · DOI
10.1161/res.86.5.494 · DOI
10.1161/circ.94.11.2756 · DOI
10.1161/circ.101.11.1261 · DOI
10.1161/circ.100.21.2131 · DOI
10.1161/hyp.30.1.57 · DOI
10.1161/res.77.3.510 · DOI
10.1161/circ.103.9.1282 · DOI
10.1161/hyp.33.6.1353 · DOI
10.1161/res.86.1.e7 · DOI
10.1161/res.86.2.e36 · DOI
10.1161/circ.104.10.1119 · DOI
10.1161/res.87.2.99 · DOI
10.1161/res.87.7.566 · DOI
10.1161/hyp.38.5.1044 · DOI
10.1161/circ.104.22.2673 · DOI
10.1161/circ.94.1.6 · DOI
10.1161/circ.97.3.237 · DOI
10.1161/atvb.22.1.6 · DOI
10.1161/atvb.20.1.185 · DOI

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The Role of Endothelial Dysfunction in Peripheral Blood Nerve Barrier: Molecular Mechanisms and Pathophysiological Implications
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BackgroundInfluential
Empagliflozin restores chronic kidney disease–induced impairment of endothelial regulation of cardiomyocyte relaxation and contraction
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“Since there is a heterogenous expression of (iNOS), the varying concentrations of NO can cause uneven perfusion [93,94].”
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“In the setting of hyperglycemia, ROS may react with eNOS-derived nitric oxide (NO) to form peroxynitrite, which can in turn oxidize the eNOS cofactor tetrahydrobiopterin leading to the generation of superoxide in preference to NO [85,86].”
Background
The Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Improves Vascular Endothelial Function in Type 2 Diabetes
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Differences in Tolerance to Hypoxia: Physiological, Biochemical, and Molecular-Biological Characteristics
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BackgroundInfluential
Endothelial Nitric Oxide Synthase in Human Intestine Resected for Necrotizing Enterocolitis
Nowicki, P. T., Caniano, D. A., Hammond, S., Giannone, P. J., Besner, G. E., Reber, K. M., & Nankervis, C. A. (2006) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2006.09.029 · Cited by 75
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“eNOS becomes uncoupled under certain circumstances such as high glucose challenge to produce superoxide instead of NO (Bauersachs and Schäfer, 2005; Forstermann and Munzel, 2006).”
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Long-term high-fat diet induces hippocampal microvascular insulin resistance and cognitive dysfunction
Fu, Z., Wu, J., Nesil, T., Li, M. D., Aylor, K. W., & Liu, Z. (2016) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00297.2016 · Cited by 74
“The marked decrease in hippocampal eNOS expression in HFD-fed rats provides further explanation of the lack of microvascular response to insulin in those animals, as eNOS is the major molecule regulating vascular tension (17, 54).”
Background
Endothelial dysfunction in individuals born after fetal growth restriction: cardiovascular and renal consequences and preventive approaches
Yzydorczyk, C., Armengaud, J.-B., Peyter, A., Chehade, H., Cachat, F., Juvet, C., Siddeek, B., Simoncini, S., Sabatier, F., Dignat‐George, F., et al. (2017) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174417000265 · Cited by 74
Histone methylation and vascular biology
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Endothelial Dysfunction in Primary Aldosteronism
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“NO is synthesized from L-arginine in the presence of cofactors including tetrahydrobiopterin (BH4) via endothelial NO synthase (eNOS), which is an enzyme expressed in endothelial cells [18].”
Background
Endothelial dysfunction of rat coronary arteries after exposure to low concentrations of mercury is dependent on reactive oxygen species
Furieri, L. B., Galán, M., Avendaño, M. S., García‐Redondo, A. B., Aguado, A., Martínez, S. G., Cachofeiro, V., Bartolomé, M. V., Alonso, M. J., Vassallo, D. V., et al. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01203.x · Cited by 73
“However, we cannot discount a possible reduction in the activity of this isoform, or that uncoupled eNOS due to tetrahydrobiopterin (BH4) deficiency might result in a switch from NO to O2 production (Förstermann and Münzel, 2006).”
Background
eNOS haplotypes affect the responsiveness to antihypertensive therapy in preeclampsia but not in gestational hypertension
Sandrim, V. C., Palei, A. C., Luizon, M. R., Izidoro‐Toledo, T. C., Cavalli, R. D. C., & Tanus-Santos, J. E. (2009) · The Pharmacogenomics Journal · doi:10.1038/tpj.2009.38 · Cited by 74
Tetrahydrocurcumin Protects against Cadmium-Induced Hypertension, Raised Arterial Stiffness and Vascular Remodeling in Mice
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Background
Randomized clinical trial on the efficacy of hesperidin 2S on validated cardiovascular biomarkers in healthy overweight individuals
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“Under circumstances where L-arginine and/or essential cofactors (tetrahydrobiopterin (BH4) are limited, NOS can uncouple to produce superoxide instead of NO (5).”
Background
The Impact of Tobacco Cigarettes, Vaping Products and Tobacco Heating Products on Oxidative Stress
Emma, R., Caruso, M., Campagna, D., Pulvirenti, R., & Volti, G. L. (2022) · Antioxidants · doi:10.3390/antiox11091829 · Cited by 89
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Background
Cardiomyocyte-restricted restoration of nitric oxide synthase 3 attenuates left ventricular remodeling after chronic pressure overload
Buys, E. S., Raher, M. J., Blake, S. L., Neilan, T. G., Graveline, A. R., Passeri, J. J., Llano, M., Pérez-Sanz, T. M., Ichinose, F., Janssens, S. P., et al. (2007) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01236.2006 · Cited by 72
“NOS3 is synthesized as monomers and dimerizes in the presence of heme (8).”
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Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways
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Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis
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“Endothelial nitric oxide synthase (eNOS) is responsible for the production of most vascular nitric oxide (NO) (96, 97).”
Background
Heme oxygenase-1 ameliorates oxidative stress-induced endothelial senescence via regulating endothelial nitric oxide synthase activation and coupling
Luo, W., Wang, Y., Yang, H., Dai, C., Hong, H., Li, J., Liu, Z., Guo, Z., Chen, X., He, P., et al. (2018) · Aging · doi:10.18632/aging.101506 · Cited by 72

Authors: Förstermann, U., & Münzel, T.
Affiliations: From the Departments of Pharmacology (U.F.) and Internal Medicine II (Cardiology) (T.M.), Johannes Gutenberg University Hospitals, Mainz, Germany.
Venue: Circulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2006-04-04
Volume: 113
Issue: 13
Pages: 1708-1714
ISSN: 0009-7322 (ISSN-L)
1524-4539
DOI: 10.1161/circulationaha.105.602532
OpenAlex: W2146190354
Cited by: 1,957
References: 67
Citations by year: 2026: 93 · 2025: 76 · 2024: 99 · 2023: 86 · 2022: 110 · 2021: 113 · 2020: 110 · 2019: 89 · 2018: 105 · 2017: 105 · 2016: 117 · 2015: 101 · 2014: 123 · 2013: 98 · 2012: 85
FWCI: 62.52
Type: journal article
Language: en
Open access: closed
Locations: Circulation (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
Keywords: endothelial nitric oxide synthase, nitric oxide, tetrahydrobiopterin, eNOS uncoupling, NADPH oxidase, reactive oxygen species, superoxide, peroxynitrite, oxidative stress, cardiovascular risk factors, hypertension, hypercholesterolemia, diabetes mellitus, smoking, folic acid, vitamin C, L-arginine
MeSH terms: Animals, Endothelium, Vascular, Humans, Nitric Oxide, Vascular Diseases, Reactive Oxygen Species, Oxidative Stress, Nitric Oxide Synthase Type III

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Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace

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