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Relationship: 982


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

Impaired, Vasodilation leads to Increase, Vascular Resistance

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 Moderate Low Brendan Ferreri-Hanberry (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
Homo sapiens Homo sapiens Moderate NCBI
Rattus norvegicus Rattus norvegicus Low NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific Not Specified

Life Stage Applicability

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

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

Vasodilation decreases systemic vascular resistance (SVR; also known previously as Total Peripheral Resistance; TPR), the resistance to blood flow offered by the peripheral circulation, and blood pressure through relaxation of vascular smooth muscle cells (VSMCs) (Siddiqui, 2011). When vasodilation is impaired due to decreased NO availability, SVR and blood pressure become elevated.

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

The overall weight of evidence for the KER was rated "moderate" due the fact that acute pharmacological manipulation of the NO pathway resulted in corresponding changes in SVR.  However, in the context of the development of hypertension, the chronic effects of impaired vasodilation are much less clear.

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

It is well-accepted that vasodilation and SVR are negatively correlated; blood flow is increased when blood vessels dilate due to a decrease in vascular resistance (Siddiqui, 2011). When vasodilation is impaired, SVR increases, in turn increasing blood pressure. Agents that cause hyperpolarization are potent vasodilators and activate potassium channels, while factors causing depolarization increase vascular tone (Nelson, 1990). Vascular tone is governed by the contractile activity of VSMCs in the walls of small arteries and arterioles, and is the major determinant of the resistance to blood flow through the circulation (Jackson, 2000). VSMCs from hypertensive animals have decreased functional voltage-gated potassium channels, which may contribute to depolarization. Two studies demonstrated that blockade of potassium channels completely inhibited NO-dependent vasodilation and increased SVR (Dessy et al., 2004; Berg et al., 2011). Inhibitors of eNOS activity (L-NAME, L-NMMA), which have been shown to decrease acetylcholine-induced vasorelaxation in animal studies (Li et al., 2007; Paulis et al., 2008), also caused an increase in SVR in human studies (Wilkinson et al., 2002; McVeigh et al., 2001; Brett et al., 1998). Overall, these results provide strong biological plausibility for this link.

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

As mentioned above, acute pharmacological manipulation of the NO pathway results in expected changes in SVR.  However, the link between chronically impaired vasodilation and SVR (the context of this AOP) is much less clear due to gaps in the literature.  Epidemiological studies tend to investigate linkages between impaired vasodilation and cardiovascular events, as opposed to SVR and/or hypertension - making assessment of this KER difficult.

Furthermore, the complexity in the mechanisms influencing vascular re-modelling over time has hampered understanding of the phenomenon to date.  The study by Modena et al. 2002 highlights that members of the general population respond differently to hypertensive therapy in the context of FMD improvement.

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 impaired vasodilation and SVR was shown in human and rat studies.


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

Berg, T., and Jensen, J. (2011). Simultaneous parasympathetic and sympathetic activation reveals altered autonomic control of heart rate, vascular tension, and epinephrine release in anesthetized hypertensive rats. Front. Neurol. 2, 71.

Brett, S.E., Cockcroft, J.R., Mant, T.G., Ritter, J.M., and Chowienczyk, P.J. (1998). Haemodynamic effects of inhibition of nitric oxide synthase and of L-arginine at rest and during exercise. J. Hypertens. 16, 429–435.

Dessy, C., Moniotte, S., Ghisdal, P., Havaux, X., Noirhomme, P., and Balligand, J.L. (2004). Endothelial beta3-adrenoceptors mediate vasorelaxation of human coronary microarteries through nitric oxide and endothelium-dependent hyperpolarization. Circulation 110, 948–954.

Eugene, A.R. (2016). The influences of nitric oxide, epinephrine, and dopamine on vascular tone: dose-response modeling and simulations. Hosp. Chron. Nosokomeiaka Chron. 11, 1–8.

Jackson, W.F. (2000). Ion channels and vascular tone. Hypertension 35, 173–178.

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.

McVeigh, G.E., Allen, P.B., Morgan, D.R., Hanratty, C.G., and Silke, B. (2001). Nitric oxide modulation of blood vessel tone identified by arterial waveform analysis. Clin. Sci. Lond. Engl. 1979 100, 387–393.

Modena MG, Bonetti L, Coppi F, Bursi F, Rossi R Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women.  J Am Coll Cardiol. 2002, 40(3):505-10.

Nelson, M.T., Patlak, J.B., Worley, J.F., and Standen, N.B. (1990). Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone. Am. J. Physiol. 259, C3–C18.

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.

Ras RT, Streppel MT, Draijer R, Zock PL.  Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis.  Int J Cardiol. 2013, 168(1):344-51.

Siddiqui, A. (2011). Effects of Vasodilation and Arterial Resistance on Cardiac Output. J. Clin. Exp. Cardiol. 02.

Stamler, J.S., Loh, E., Roddy, M.A., Currie, K.E., and Creager, M.A. (1994). Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans. Circulation 89, 2035–2040.

Wilkinson, I.B., MacCallum, H., Cockcroft, J.R., and Webb, D.J. (2002). Inhibition of basal nitric oxide synthesis increases aortic augmentation index and pulse wave velocity in vivo. Br. J. Clin. Pharmacol. 53, 189–192.

Yeboah J, Crouse JR, Hsu FC, Burke GL, Herrington DM.  Brachial flow-mediated dilation predicts incident cardiovascular events  in older adults: the Cardiovascular Health Study. Circulation. 2007;115:2390–7.