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Relationship: 958


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Depletion, Nitric Oxide leads to Impaired, Vasodilation

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Peptide Oxidation Leading to Hypertension adjacent High Moderate Frazer Lowe (send email) Not under active development Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Mus musculus Mus musculus High NCBI
Oryctolagus cuniculus Oryctolagus cuniculus Moderate NCBI
Rattus norvegicus Rattus norvegicus High NCBI
Homo sapiens Homo sapiens High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Nitric oxide (NO) is a critical endothelium-derived hyperpolarising factor (EDHF), responsible for relaxation of vascular smooth muscle and vasodilation.  The primary regulator of endothelial vasodilator function via NO is vascular shear; the frictional force exerted on the vascular wall during the flow of blood through the vessel. Vascular shear opens calcium channels on endothelial cells, and leads to the calcium-dependent activation of eNOS and thus NO production.  NO then diffuses to the underlying vascular smooth muscle, where it activates soluble guanylate cyclase, causing an increase in cyclic guanosine monophosphate (cGMP), potassium ion efflux, hyperpolarization and smooth muscle relaxation (Giles et al. 2012).

Depletion of vascular NO bioavailability causes an imbalance in the maintenance of vascular tone, which shifts in favour of vasoconstriction, and hence elevates blood pressure (Kojda et al. 1999).  Under oxidative stress, decreased NO bioavailability results in impaired endothelium-dependent vasodilation (Silva et al., 2012).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Vasodilation is caused by the relaxation of vascular smooth muscle cells within the walls of blood vessels, which is regulated through a number of mechanisms, including cyclic GMP-dependent hyperpolarization and relaxation via NO. Thus, alterations to NO levels have an influence on vasodilation (Silva et al., 2012). Many animal studies demonstrated that inhibition of NO via eNOS inhibitors impaired acetylcholine-induced endothelium-dependent vasodilation, providing strong biological plausibility for this key event relationship.

Constitutively active AKT, which has been shown to phosphorylate and activate eNOS, increased resting vessel diameter in a rabbit femoral artery model, but infusion with eNOS inhibitor L-NAME reversed this effect (Luo et al., 2000). Dominant negative AKT, which prevents eNOS activation, also blocked vasodilation in response to the endothelium-dependent agonist acetylcholine (ACh) in rabbit arteries and mouse aortas. Since acetylcholine induces endothelium-dependent vasodilation, the assumption is that when eNOS inhibitors blocks Ach-induced vasodilation, NO production is decreased and vasodilation is impaired. L-NAME abolished endothelium-dependent relaxations induced by ACh in aortas of wild-type and hph-1 mice (Li et al., 2007). ACh induced a dose-dependent endothelium-dependent relaxation in rat small mesenteric arteries, but the NO-dependent component of ACh-induced relaxation was decreased in L-NAME-treated rats (Paulis et al., 2008). After L-NAME cessation, the NO-dependent component was restored to above control levels. L-NAME diminished eNOS activity by 66% and its cessation restore NOS activity to control levels in rat aortas. Another study showed that L-NAME caused a mild but significant decrease in vasodilation in rat thoracic aorta (Sélley et al., 2014).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

While the effect of NO depletion on impaired vasodilation is clear, the NO pathway does not appear to be solely responsible for this phenomenon.  Vascular tone is a balance between relaxation and constriction factors.  Studies have shown that when NO bioavailability is decreased, COX-mediated pro-inflammatory factors such as prostaglandins (Kellogg et al. 2005, Lüscher and Vanhoutte 1986) and Endothelin-1 (Taddei et al. 2003)  contribute to a shift in vascular tone towards vasoconstiction.  The review by Silva et al. (2012) discusses the roles of various pathways and their effects on vascular tone.  The relative contribution of these mechanisms towards vascular tone is currently unknown.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

This relationship between NO depletion and impaired vasodilation was shown in humans (Li et al. 1993, Heitzer et al. 2000), rabbits (Luo et al. 2000), mice (Luo et al. 2000, Wang et al. 2008) and rats (Paulis et al. 2008, Li et al. 1993, Sélley et al. 2014, Chen et al. 2010).


List of the literature that was cited for this KER description. More help

Bode-Böger SM, Böger RH, Galland A, Tsikas D, Frölich JC.  L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamicrelationship.  Br J Clin Pharmacol. 1998, 46(5):489-97.

Carnevale R, Sciarretta S, Violi F et al.  Acute Impact of Tobacco vs Electronic Cigarette Smoking on Oxidative Stress and Vascular Function.  Chest. (2016) 150(3):606-12.

Chen, C.-A., Wang, T.-Y., Varadharaj, S., Reyes, L.A., Hemann, C., Talukder, M.A.H., Chen, Y.-R., Druhan, L.J., and Zweier, J.L. (2010). S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature 468, 1115–1118.

Giles TD, Sander GE, Nossaman BD et al. Impaired vasodilation in the pathogenesis of hypertension: focus on nitric oxide, endothelial-derived hyperpolarizing factors, and prostaglandins.  J Clin Hypertens (2012) 14(4):198-205.

Heitzer T, Brockhoff C, Mayer B, Warnholtz A, Mollnau H, Henne S, Meinertz T, Münzel T.  Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers : evidence for a dysfunctional nitric oxide synthase.  Circ Res. 2000, 86(2):E36-41.

Kellogg DL Jr, Zhao JL, Coey U, Green JV.  Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin.  J Appl Physiol (1985). 2005, 98(2):629-32.

Kojda G, Laursen JB, Ramasamy S et al. Protein expression, vascular reactivity and soluble guanylate cyclase activity in mice lacking the endothelial cell nitric oxide synthase: contributions of NOS isoforms to blood pressure and heart rate control.  Cardiovasc Res. (1999) 42(1):206-13.

Li, J., Zhou, Z., Jiang, D.-J., Li, D., Tan, B., Liu, H., and Li, Y.-J. (2007). Reduction of NO- and EDHF-mediated vasodilatation in hypertension: role of asymmetric dimethylarginine. Clin. Exp. Hypertens. N. Y. N 1993 29, 489–501.

Lüscher T. F., Vanhoutte P. M. (1986). Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension 8, 344–348

Luo, Z., Fujio, Y., Kureishi, Y., Rudic, R.D., Daumerie, G., Fulton, D., Sessa, W.C., and Walsh, K. (2000). Acute modulation of endothelial AKT/PKB activity alters nitric oxide–dependent vasomotor activity in vivo. J. Clin. Invest. 106, 493–499.

Paulis, L., Zicha, J., Kunes, J., Hojna, S., Behuliak, M., Celec, P., Kojsova, S., Pechanova, O., and Simko, F. (2008). Regression of L-NAME-induced hypertension: the role of nitric oxide and endothelium-derived constricting factor. Hypertens. Res. Off. J. Jpn. Soc. Hypertens. 31, 793–803.

Sander M, Chavoshan B, Victor RG.  A large blood pressure-raising effect of nitric oxide synthase inhibition in humans.  Hypertension. (1999) 33(4):937-42.

Sélley, E., Kun, S., Szijártó, I.A., Laczy, B., Kovács, T., Fülöp, F., Wittmann, I., and Molnár, G.A. (2014). Exenatide induces aortic vasodilation increasing hydrogen sulphide, carbon monoxide and nitric oxide production. Cardiovasc. Diabetol. 13, 69.

Silva, B.R., Pernomian, L., and Bendhack, L.M. (2012). Contribution of oxidative stress to endothelial dysfunction in hypertension. Front. Physiol. 3, 441.

Taddei S., Ghiadoni L., Virdis A., Versari D., Salvetti A. (2003). Mechanisms of endothelial dysfunction: clinical significance and preventive non-pharmacological therapeutic strategies. Curr. Pharm. Des. 9, 2385–2402

Taylor BA, Zaleski AL, Dornelas EA et al.  The impact of tetrahydrobiopterin administration on endothelial function before and after smoking cessation in chronic smokers.  Hypertens Res. (2016) 39(3):144-50.

Wang, S., Xu, J., Song, P., Wu, Y., Zhang, J., Chul Choi, H., and Zou, M.-H. (2008). Acute inhibition of guanosine triphosphate cyclohydrolase 1 uncouples endothelial nitric oxide synthase and elevates blood pressure. Hypertension 52, 484–490.