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
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10.1161/circ.94.11.2756 · DOI
10.1161/circ.101.11.1261 · DOI
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10.1161/hyp.30.1.57 · DOI
10.1161/res.77.3.510 · DOI
10.1161/circ.103.9.1282 · DOI
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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
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10.1161/atvb.22.1.6 · DOI
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“In addition, mechanistic variables that affect VEF, namely endothelin-1 [60], and oxidative stress [61], both exhibited circadian rhythms with an increase across the morning hours and a peak around noon [1].”
Background
Genetic Elimination of eNOS Reduces Secondary Complications of Experimental Subarachnoid Hemorrhage
Sabri, M., Ai, J., Lass, E., D’Abbondanza, J. A., & Macdonald, R. L. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.49 · Cited by 48
Anemia in Heart Failure Patients
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“Endothelial dysfunction associated with heart failure may alter endothelial NO synthase activity, hence further augmenting myocardial dysfunction due to increased oxidative stress [54].”
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Pathological Cardiac Hypertrophy Alters Intracellular Targeting of Phosphodiesterase Type 5 From Nitric Oxide Synthase-3 to Natriuretic Peptide Signaling
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The anti-inflammatory effect of Agaricus brasiliensis is partly due to its linoleic acid content
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FGF23 impairs peripheral microvascular function in renal failure
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Monomeric C‐reactive protein via endothelial CD31 for neurovascular inflammation in an ApoE genotype‐dependent pattern: A risk factor for Alzheimer’s disease?
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Reactive Oxygen Species and Oxidative Stress in the Pathogenesis and Progression of Genetic Diseases of the Connective Tissue
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“This process is known as eNOS uncoupling [65].”
Background
Noise, Air, and Heavy Metal Pollution as Risk Factors for Endothelial Dysfunction
Jiménez, M. T. B., Hahad, O., Kuntić, M., Daiber, A., & Münzel, T. F. (2023) · European Cardiology Review · doi:10.15420/ecr.2022.41 · Cited by 48
Activation of endothelial TRPM2 exacerbates blood–brain barrier degradation in ischemic stroke
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Acute localized administration of tetrahydrobiopterin and chronic systemic atorvastatin treatment restore cutaneous microvascular function in hypercholesterolaemic humans
Holowatz, L. A., & Kenney, W. L. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.212100 · Cited by 47
“NOS3, which is normally dimerized, uncouples to a monomeric form without adequate substrate (Forstermann & Munzel, 2006), induced by upregulated arginase activity (Lim et al. 2007; Kim et al. 2009) or cofactor availability, and produces superoxide instead of NO (Moens & Kass, 2006).”
Background
Spironolactone treatment attenuates vascular dysfunction in type 2 diabetic mice by decreasing oxidative stress and restoring NO/GC signaling
Silva, M. A. B., Bruder-Nascimento, T. B., Cáu, S. B. D. A., Alves-Lopes, R., Mestriner, F., Fais, R. S., Touyz, R. M., & Tostes, R. C. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00269 · Cited by 48
“…mice by decreasing oxidative stress and restoring NO/GC signaling Marcondes A. B. Silva 1, Thiago Bruder-Nascimento 1, Stefany B. A. Cau 1, Rheure A. M. Lopes 1, Fabiola L. A. C. Mestriner 1, Rafael S. Fais 1, Rhian M. Touyz 2 and Rita C. Tostes 1* 1Department of Pharmacology, Ribeirao Preto…”
BackgroundInfluential
Nitric Oxide is a Central Common Metabolite in Vascular Dysfunction Associated with Diseases of Human Pregnancy
Leiva, A., Fuenzalida, B., Barros, E., Sobrevia, B., Salsoso, R., Sáez, T., Villalobos-Labra, R., Silva, L., Chiarello, D. I., Toledo, F., et al. (2016) · Current Vascular Pharmacology · doi:10.2174/1570161114666160222115158 · Cited by 50
Electrospun fibrinogen-PLA nanofibres for vascular tissue engineering
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“Interestingly, although cells grew equally well on both type of nanofibres (Table 1), randomly orientated nanofibres provoked endothelial cells to produce significantly more NO, allowing the cells to better influence local vessel contractility and platelet activation (Förstermann and Münzel, 2006).”
Background
Melatonin mediates vasodilation through both direct and indirect activation of BKCa channels
Zhao, T., Zhang, H., Jin, C., Qiu, F., Wu, Y. H., & Shi, L. (2017) · Journal of Molecular Endocrinology · doi:10.1530/jme-17-0028 · Cited by 47
Oxidative burden in familial hypercholesterolemia
Mollazadeh, H., Carbone, F., Montecucco, F., Pirro, M., & Sahebkar, A. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26466 · Cited by 48
“According to experimental evidence, hypercholesterolemia was associated with reduced serum levels of BH4 and positively correlated with superoxide generation and OS (Prasanna &Purnima, 2011; Stroes et al., 1997).”
Background
Evidence of epigenetic alterations in thrombosis and coagulation: A systematic review
Patsouras, M., & Vlachoyiannopoulos, P. G. (2019) · Journal of Autoimmunity · doi:10.1016/j.jaut.2019.102347 · Cited by 47
Ubiquinol Ameliorates Endothelial Dysfunction in Subjects with Mild-to-Moderate Dyslipidemia: A Randomized Clinical Trial
Sabbatinelli, J., Orlando, P., Galeazzi, R., Silvestri, S., Cirilli, I., Marcheggiani, F., Dludla, P. V., Giuliani, A., Bonfigli, A. R., Mazzanti, L., et al. (2020) · Nutrients · doi:10.3390/nu12041098 · Cited by 47
“The endothelium modulates the vascular tone mainly through nitric oxide (NO) synthesis by the endothelial isoform of NO synthase (eNOS) [9,10].”
Background
Amino Acid Signature of Oxidative Stress in Patients with Type 2 Diabetes: Targeted Exploratory Metabolomic Research
Bala, C. G., Rusu, A., Ciobanu, D. M., Bucșa, C., & Román, G. (2021) · Antioxidants · doi:10.3390/antiox10040610 · Cited by 47
“NO is a key mediator in the regulation of vascular tone, platelet aggregation and vascular smooth cell proliferation, and thus, reduced NO levels are contributing factors to endothelial dysfunction in diabetes [35].”
Background
Soluble Angiotensin Converting Enzyme 2 (ACE2) Is Upregulated and Soluble Endothelial Nitric Oxide Synthase (eNOS) Is Downregulated in COVID-19-induced Acute Respiratory Distress Syndrome (ARDS)
Vassiliou, A. G., Zacharis, A., Keskinidou, C., Jahaj, E., Pratikaki, M. E., Gallos, P., Dimopoulou, I., Kotanidou, Α., & Orfanos, S. E. (2021) · Pharmaceuticals · doi:10.3390/ph14070695 · Cited by 47
“Experimental studies in various lung injury models have demonstrated that increased levels of eNOS-derived NO are associated with beneficial effects [6–14], while the high bioavailability of NO from inducible NO synthase (iNOS) may aggravate lung injury [15,16].”
Background
Beneficial Effects of Exogenous Tetrahydrobiopterin on Left Ventricular Remodeling After Myocardial Infarction in Rats The Possible Role of Oxidative Stress Caused by Uncoupled Endothelial Nitric Oxide Synthase
Masano, T., Kawashima, S., Toh, R., Satomi‐Kobayashi, S., Shinohara, M., Takaya, T., Sasaki, N., Takeda, M., Tawa, H., Yamashita, T., et al. (2008) · Circulation Journal · doi:10.1253/circj.cj-08-0072 · Cited by 47
On to the road to degradation: atherosclerosis and the proteasome
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“It has been postulated that superoxide production by the stimulation of NADPH oxidases would be the primary process to reduce BH4.”
BackgroundInfluential
Comparison of the Antihypertensive Activity of Phenolic Acids
Yu, M., Kim, H., Heo, H., Kim, M.-J., Jeon, Y., Lee, H., & Lee, J. (2022) · Molecules · doi:10.3390/molecules27196185 · Cited by 46
“Nuclear factor-E2-related factor 2 (Nrf2), an antioxidant transcription factor important in CVD resistance [6], is highly sensitive to oxidative damage.”
Background
ADMA injures the glomerular filtration barrier: role of nitric oxide and superoxide
Sharma, M., Zhou, Z., Miura, H., Papapetropoulos, A., McCarthy, E. T., Sharma, R., Savin, V. J., & Lianos, E. A. (2009) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.90369.2008 · Cited by 48
“NOS uncoupling may also result from insufficient levels of (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4) due to decreased synthesis or increased oxidation to BH2 (8, 30).”
Background
Culture of Human Endothelial Cells from Umbilical Veins
Siow, R. C. M. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-367-7_18 · Cited by 46
Redox Mechanisms in Migraine: Novel Therapeutics and Dietary Interventions
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“…in brain structures involved in headache (247, 385, 397) and by the implied role for NO in vascular tone regulation (201, 363), platelet activity (108), neuronal excitability and sensitization (290, 385), nociception (72, 215), allodynia (208), and migraine neurotrans-mission (247), has been…”
A Computational Systems Pharmacology Approach to Investigate Molecular Mechanisms of Herbal Formula Tian-Ma-Gou-Teng-Yin for Treatment of Alzheimer’s Disease
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“Nitric oxide plays a key role in the regulation of many physiological processes, such as vasodilation, inﬂammation, and neurodegeneration (Förstermann and Münzel, 2006; Brown, 2010).”
Background
High glutathionylation of placental endothelial nitric oxide synthase in preeclampsia
Guerby, P., Swiader, A., Augè, N., Parant, O., Vayssière, C., Uchida, K., Salvayre, R., & Nègre‐Salvayre, A. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101126 · Cited by 49
“For instance, eNOS polymorphism (G894T and T-786C) [21,22], or eNOS uncoupling [17,23,24], have been associated with an increased risk of PE.”
Background
The Nitric Oxide Pathway in Pulmonary Arterial Hypertension: Pathomechanism, Biomarkers and Drug Targets
Lázár, Z., Mészáros, M., & Bikov, A. (2020) · Current Medicinal Chemistry · doi:10.2174/0929867327666200522215047 · Cited by 47
Pathophysiology of the no-reflow phenomenon
Vrints, C. J. (2009) · Acute Cardiac Care · doi:10.1080/17482940902978061 · Cited by 46
Catechins and Proanthocyanidins Involvement in Metabolic Syndrome
Patanè, G. T., Putaggio, S., Tellone, E., Barreca, D., Ficarra, S., Maffei, C., Calderaro, A., & Laganà, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119228 · Cited by 45
Regulation of endothelial function by cigarette smoke and next-generation tobacco and nicotine products
Klein, J., Diaba‐Nuhoho, P., Giebe, S., Brunßen, C., & Morawietz, H. (2023) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-023-02824-w · Cited by 45
“The oxidation of (6R)-5,6,7,8-tetrahydro-L-biopterin, a cofactor of the eNOS [27, 31], leads to uncoupling of the eNOS enzymes regularly acting as dimers [26, 57].”
Background
Effect of long-term piceatannol treatment on eNOS levels in cultured endothelial cells
Kinoshita, Y., Kawakami, S., Yanae, K., Sano, S., Uchida, H., Inagaki, H., & Ito, T. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.12.017 · Cited by 45
Endothelial Nitric Oxide Synthase Gene G894T Polymorphism and Myocardial Infarction: A Meta-Analysis of 34 Studies Involving 21068 Subjects
Luo, J., Wen, J., Zhou, H., Chen, X., & Zhang, W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087196 · Cited by 45
Endothelial Dysfunction and Coronary Artery Disease
Veerasamy, M., Bagnall, A. J., Neely, D., Allen, J., Sinclair, H., & Kunadian, V. (2014) · Cardiology in Review · doi:10.1097/crd.0000000000000047 · Cited by 45
“NO is generated from l-arginine constitutively by endothelial NO synthase (eNOS) and diffuses through to adjacent vascular smooth muscle cells to activate guanylate cyclase, which in turn leads to cyclic guanosine monophosphate-mediated vasodilatation.(10) Asymmetric dimethyl arginine (ADMA) is a potent competitive in…”
Background
Endothelial NOS (NOS3) impairs myocardial function in developing sepsis
van de Sandt, A. M., Windler, R., Gödecke, A., Ohlig, J., Zander, S., Reinartz, M. T., Graf, J., van Faassen, E. E., Rassaf, T., Schrader, J., et al. (2013) · Basic Research in Cardiology · doi:10.1007/s00395-013-0330-8 · Cited by 47
“NOS3 itself can be a superoxide source, thereby causing endothelial dysfunction [14].”
Background
Astragaloside IV improves the isoproterenol-induced vascular dysfunction via attenuating eNOS uncoupling-mediated oxidative stress and inhibiting ROS-NF-κB pathways
Xu, C., Tang, F., Lü, M., Yang, J., Han, R., Mei, M., Hu, J., Zhou, M.-S., & Wang, H. (2016) · International Immunopharmacology · doi:10.1016/j.intimp.2016.02.009 · Cited by 45
Investigation of the role of nitric oxide driven angiogenesis by zinc oxide nanoflowers
Barui, A. K., Nethi, S. K., & Patra, C. R. (2017) · Journal of Materials Chemistry B · doi:10.1039/c6tb03323g · Cited by 46
miRNA Involvement in Cerebral Ischemia-Reperfusion Injury
Neag, M. A., Mitre, A. O., Burlacu, C.-C., Inceu, A.-I., Mihu, C., Melincovici, C. S., Bichescu, M., & Buzoianu, A. D. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.901360 · Cited by 44
Suppression of Diet-Induced Hypercholesterolemia by Scutellarin in Rats
Li, Q., Wu, J.-H., Guo, D.-J., Cheng, H.-L., Chen, S., & Chan, S. (2009) · Planta Medica · doi:10.1055/s-0029-1185539 · Cited by 44
Alterations of NOS, arginase, and DDAH protein expression in rabbit cavernous tissue after administration of cigarette smoke extract
Imamura, M., Waseda, Y., Marinova, G. V., Ishibashi, T., Obayashi, S., Sasaki, A., Nagai, A., & Azuma, H. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00406.2007 · Cited by 44
“However, it is still possible that free radical(s) rather than NO is produced as a result of “NOS uncoupling” (19) due to accumulation of endogenous NOS inhibitors as described below.”
Background
Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs
Grasemann, H., Dhaliwal, R., Ivanovska, J., Kantores, C., McNamara, P. J., Scott, J. A., Belik, J., & Jankov, R. P. (2015) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00328.2014 · Cited by 44
Spatial and temporal patterns of nitric oxide diffusion and degradation drive emergent cerebrovascular dynamics
Haselden, W. D., Kedarasetti, R. T., & Drew, P. J. (2020) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1008069 · Cited by 47
The Critical Role of Tetrahydrobiopterin (BH4) Metabolism in Modulating Radiosensitivity: BH4/NOS Axis as an Angel or a Devil
Feng, Y., Feng, Y., Gu, L., Liu, P., Cao, J., & Zhang, S. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.720632 · Cited by 44
“Suboptimal levels of BH4 due to the oxidation to BH2 via stimuli such as radiation exposure may lead to NOS uncoupling and the subsequent generation of highly oxidative radicals, including superoxide and peroxynitrite (77), which is the main mechanism of impaired vascular regulation (78).”
Background
Oxidative stress and endothelial dysfunction
de Dios, S. T., Sobey, C. G., & Drummond, G. R. (2010) · Springer eBooks · doi:10.1007/978-3-0346-0168-9_3 · Cited by 44
Cigarette smoke and LDL cooperate in reducing nitric oxide bioavailability in endothelial cells via effects on both eNOS and NADPH oxidase
Steffen, Y., Vuillaume, G., Stolle, K., Röwer, K., Lietz, M., Schueller, J., Lebrun, S., & Wallerath, T. (2012) · Nitric Oxide · doi:10.1016/j.niox.2012.06.006 · Cited by 44
Drugs targeting nitric oxide synthase for migraine treatment
Barbanti, P., Egeo, G., Aurilia, C., Fofi, L., & Della‐Morte, D. (2014) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2014.918953 · Cited by 44
“No research has developed selective eNOS inhibitors insofar as they are probably unsuitable for clinical application given this enzyme’s crucial involvement in the homeostatic regulation of numerous essential cardiovascular functions [14].”
Background
Inhibition of p38 MAPK reverses hypoxia-induced pulmonary artery endothelial dysfunction
Weerackody, R. P., Welsh, D., Wadsworth, R. M., & Peacock, A. J. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00977.2008 · Cited by 44
“The uncoupling of eNOS leads to production of superoxide anion instead of NO and is increasingly appreciated as an important source of superoxide anion in the pathogenesis of cardiovascular disorders (15).”
Background
Acute hypoxia to endothelial cells induces activating transcription factor 3 (ATF3) expression that is mediated via nitric oxide
Chen, S.-C., Liu, Y., Shyu, K., & Wang, D. L. (2008) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2008.02.014 · Cited by 43
Nitric oxide synthase 3 contributes to ventilator-induced lung injury
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Novel Therapies Targeting Vascular Endothelium
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Cervical Ganglion Block Attenuates the Progression of Pulmonary Hypertension via Nitric Oxide and Arginase Pathways
Na, S., Kim, O. S., Ryoo, S., Kweon, T. D., Choi, Y. S., Shim, H. S., & Oh, Y. J. (2013) · Hypertension · doi:10.1161/hypertensionaha.113.01979 · Cited by 44
“organ, secreting vasoactive mediators under neurohumoral control.(3) It has been demonstrated that autonomic nerves and the endothelium work together to maintain vascular tone,(16)”
BackgroundInfluential

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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