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Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace
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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“The uncoupling causes eNOS activity to change from healthy (producing NO) to toxic (generating superoxide) (303).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [303]
In the citing paper
“Similarly, vascular disease, cardiovascular disease (CVD), and metabolic syndrome all share effective loss of NO function[23,35–39].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [23]
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“Endogenous ROS increase with aging and are capable of readily reacting with NO to form peroxynitrite (ONOO ), which limits NO-dependent vasodilation and may potentially serve as a vasoconstrictor stimulus (19).”
Endothelial dysfunction and cardiovascular risk factors
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“vasoactive peptides such as angiotensin II, norepinephrine, and serotonin; participates actively in leukocyte and platelet activation; and facilitates a prothrombotic and proatherogenic phenotype [5–9].”
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Dysfunction of Cerebrovascular Endothelial Cells: Prelude to Vascular Dementia
Wang, F., Cao, Y., Ma, L., Pei, H., Rausch, W., & Li, H. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00376 · Cited by 163
“ROS can decrease eNOS activity through the Ras homolog gene family member A(RhoA) pathway (Forstermann and Munzel, 2006).”
BackgroundTousoulis, D., Andreou, I., Antoniades, C. A., Tentolouris, C. A., & Stefanadis, C. (2008) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2008.05.034 · Cited by 157
Pathogenetic role of eNOS uncoupling in cardiopulmonary disorders
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“Mutation in this cluster prevents the binding of zinc, BH4, or L-arginine and eliminates enzyme activity [49], suggesting that stabilization of the dimer interface by the zinc thiolate center is one of the keys for”
BackgroundHemoglobin Redox Reactions and Red Blood Cell Aging
Rifkind, J. M., & Nagababu, E. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4867 · Cited by 156
“PN is also generated in the interstitial spaces of the endothelium by the reaction of superoxide generated by NADPH oxidases, xanthine oxidase, and uncoupled e-NOS, which reacts with NO generated by e-NOS (33, 78).”
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The impact of reactive oxygen species in the development of cardiometabolic disorders: a review
Akhigbe, R. E., & Ajayi, A. F. (2021) · Lipids in Health and Disease · doi:10.1186/s12944-021-01435-7 · Cited by 165
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Oxidative Stress and Antioxidants in Atherosclerosis Development and Treatment
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“Moreover, activation of iNOS may result in relative deficiency of BH4 for eNOS, thereby uncoupling eNOS, and forming a major source of ROS that contributes to atherogenesis.”
BackgroundInfluentialTNF-α Contributes to Endothelial Dysfunction by Upregulating Arginase in Ischemia/Reperfusion Injury
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“Our results show that: (1) I/R decreased NOS activity in WT mice, but I/R did not further decrease NOS activity in TNF/ mice and I/R did not affect NOS activity in TNF/ mice; ( 2 ) protein expression of eNOS was decreased in I/R versus sham, in WT and TNF/ mice.”
Prevention of Atherosclerosis by Interference with the Vascular Nitric Oxide System
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“Several mechanisms may be involved in this action [33, 143]: (i) direct interaction of 5-methyltetrahydrofolate with eNOS; (ii) enhancement of BH4 binding to eNOS; (iii) chemical stabilization of BH4; and (iv) augmentation of BH4 regeneration from quinonoid BH2.”
BackgroundInfluentialMetabolic reprogramming, oxidative stress, and pulmonary hypertension
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“Uncoupling occurs when the flow of electrons from NADPH becomes uncoupled from •NO production such that the ferrous-dioxygen complex dissociates, and O2• is generated from the oxygenase domain instead of •NO [183] (Fig.”
BackgroundEndothelial Nitric Oxide Synthase Mediates Lymphangiogenesis and Lymphatic Metastasis
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“Not only is NO removed (leading to increased vasoconstriction and thus hypoxia and further ROS generation, as well as mechanic injury to the vessel due to elevated blood pressure) but NO synthase activity is also compromised, resulting in even further ROS generation (Forstermann and Münzel, 2006).”
BackgroundPulmonary Nanoparticle Exposure Disrupts Systemic Microvascular Nitric Oxide Signaling
Nurkiewicz, T. R., Porter, D. W., Hubbs, A. F., Stone, S., Chen, B. T., Frazer, D. G., Boegehold, M. A., & Castranova, V. (2009) · Toxicological Sciences · doi:10.1093/toxsci/kfp051 · Cited by 149
“An elevation of local ROS may potentially consume endothelium derived NO and result in peroxynitrite radical formation (Forstermann and Munzel, 2006).”
BackgroundMethodAntioxidant and Prooxidant Nanozymes: From Cellular Redox Regulation to Next‐Generation Therapeutics
Singh, N., Sherin, G. R., & Mugesh, G. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202301232 · Cited by 152
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Oxidative Stress in Ischemic Heart Disease
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Stabilisation of atherosclerotic plaques
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“Under these circumstances, eNOS becomes no longer the source of NO but rather superoxide anions (so-called “eNOS uncoupling”) (96).”
BackgroundOxidative stress-induced apoptosis and autophagy: Balancing the contrary forces in spermatogenesis
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“ROS have also been reported to attenuate the protective effect of NO [20] and to mediate the activation of endothelial cells and expression of adhesion molecules induced by LPS or pro-inflammatory cytokines [49,54].”
BackgroundAging and the control of human skin blood flow
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“In diabetes, the function of eNOS is altered such that the enzyme produces superoxide anion (O2 – ) rather than NO (2).”
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“…et al. 1998; Morland et al. 2017; Schobersberger et al. 2000; Tang et al. 2010), and promotes EPCs and eNOS (Gertz et al. 2006), which support the maintenance of the vascular endothelium (Förstermann and Münzel 2006) and further contribute to angiogenesis (Gertz et al. 2006; Morland et al. 2017).”
BackgroundReactive Oxygen Species in Pulmonary Vascular Remodeling
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Metadata
- 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
- Published
- 2006-04-04
- Volume
- 113
- Issue
- 13
- Pages
- 1708-1714
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- 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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