Relationship: 982



Impaired, Vasodilation leads to Increase, Vascular Resistance

Upstream event


Impaired, Vasodilation

Downstream event


Increase, Vascular Resistance

Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Adjacency Weight of Evidence Quantitative Understanding
Peptide Oxidation Leading to Hypertension adjacent Moderate Low

Taxonomic Applicability


Term Scientific Term Evidence Link
Homo sapiens Homo sapiens Moderate NCBI
Rattus norvegicus Rattus norvegicus Low NCBI

Sex Applicability


Sex Evidence
Unspecific Not Specified

Life Stage Applicability


Term Evidence
All life stages Low

Key Event Relationship Description


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 Supporting this KER


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


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.

Empirical Evidence


Include consideration of temporal concordance here

No direct evidence was found for this linkage; thus the empirical support is weak. One study indirectly showed a relationship between NO depletion and SVR, where infusion of L-NMMA (1.0 mg/kg/min) caused an increase in SVR by 63% and a 65% reduction in NO in 11 healthy volunteers after three minutes (Stamler et al., 1994). In rat small mesenteric arteries, treatment with L-NAME for five weeks decreased NO-dependent relaxation from 30% to less than 10%, but increased systolic and diastolic blood pressure to 26% and 40%, respectively (Paulis et al, 2008). Meta-analysis of clinical trials showing that infusion of the NO donor sodium nitroprusside led to a dose-dependent reduction in SVR (Eugene et al., 2016).  In a study of 400 post-menopausal women with mild-moderate hypertension and impaired FMD, anti-hypertensive therapy for 6 months was shown to improve FMD by >10% in 250 women, whereas in 150 women, FMD did not significantly change (<10% change, Modena et al. 2002).  Whilst the study demonstrates a linkage between vasodilation and hypertension in a large proportion of the study population, it raises a question regarding causality i.e. did NO-independent medication lower blood pressure, which in turn improved FMD?  Furthermore, over a third of the population showed no change.  It is possible that the medications used directly influenced key components of the NO (or other) pathways.  Since the study did not elaborate on the medicatons used by the study cohort, this is impossible to determine.

Uncertainties and Inconsistencies


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.

Quantitative Understanding of the Linkage


Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

There is very limited quantitative understanding of this linkage, however the evidence is directed towards "cardiovascular events", as opposed to specifically SVR and/or hypertension.  A meta analysis by Ras et al. (2013) stated that "a 1% increase in FMD corresponds to a 14% decrease in future CVD events.".  A total of 23 studies including 14,753 subjects were eligible for inclusion in the meta-analysis. For studies reporting continuous risk estimates, the pooled overall CVD risk was 0.92 (95%CI: 0.88; 0.95) per 1% higher FMD. The observed association seemed stronger (P-value<0.01) in diseased populations than in asymptomatic populations (0.87 (95%CI: 0.83; 0.92) and 0.96 (95%CI: 0.92; 1.00) per 1% higher FMD, respectively). For studies reporting categorical risk estimates, the pooled overall CVD risk for high vs. low FMD was similar in both types of populations, on average 0.49 (95%CI: 0.39; 0.62).

Similarly, Yeboah et al. (2007) concluded that FMD was a predictor of future cardiovascular (CVD) events and that systolic blood pressure per unit S.D. was a signficant (p=0.02) risk factor.  However, they reported that FMD added little to current risk prediction scores for future CVD events.

Response-response Relationship




Known modulating factors


Known Feedforward/Feedback loops influencing this KER


Domain of Applicability


This relationship between impaired vasodilation and SVR was shown in human and rat studies.



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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.

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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
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