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Event: 2068

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, Endothelial Dysfunction

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Increase, Endothelial Dysfunction
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
endothelium

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Deposition of energy leads to vascular remodeling KeyEvent Vinita Chauhan (send email) Under development: Not open for comment. Do not cite

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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
rat Rattus norvegicus Moderate NCBI
mouse Mus musculus Moderate NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

The endothelium is the innermost lining of blood vessels consisting of a single layer of endothelial cells and playing a critical role in the functioning of the cardiovascular system. As the layer separating blood and vessel walls, the endothelium controls the flow of molecules, fluid, and circulating blood cells between the two. Under stress conditions, the endothelium can become activated as part of a balanced immune response. However, a prolonged state of activation is problematic and what is referred to as endothelial dysfunction.  Since the endothelium is largely responsible for controlling fluid flow, dysfunctions in the endothelium can lead to fluid imbalance, blood pressure changes, and blood clot formation. Endothelial dysfunction, indicated by premature endothelial cell senescence, apoptosis, and impaired contractile response, is commonly considered a hallmark for the development of various diseases such as cardiovascular dysfunction (Deanfield et al., 2005; Konukoglu & Uzun, 2017; Korpela & Liu, 2014). 

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Assay

Reference

Description

OECD Approved Assay

Senescence-associated beta-galactosidase staining (SA-beta-gal)

(Farhat, N. et al., 2008; Noren Hooten et al., 2017)

Can be used to measure senescence-associated β-galactosidase activity, a marker for senescent cells.

No

Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay 

(Kressel & Groscurth, 1994)

Late-stage apoptosis is detected with the TUNEL method to assay the endonuclease cleavage products by enzymatically end-labeling the DNA strand breaks. 

This assay is best used in combination with others as it can provide false positives from cells undergoing DNA repair or necrosis.

Yes 

Concentration response curves to vasodilators/vasoconstrictors

(Deanfield, J. et al., 2005; Verma, S. et al., 2003)

Measurement of endothelial relaxation/contraction of blood vessels can give insight into endothelial dysfunction. This can be induced by endothelium-independent stimuli to stimulate vasodilation or vasoconstriction. A decreased stimuli response can be indicative of endothelial dysfunction. 

No

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Taxonomic applicability: Endothelial dysfunction is applicable to vertebrates as only vertebrates have a true endothelial lining (Yano et al., 2007).

Life stage applicability: This key event is not life stage specific (Chang et al., 2017; Lee et al., 2020).

Sex applicability: This key event is not sex specific (Hughson et al., 2018; Lee et al., 2020).

Evidence for perturbation by a stressor: Multiple studies show that endothelial dysfunction can be triggered by many types of stressors including ionizing radiation and altered gravity (Cheng et al., 2017; Soucy et al., 2011; Su et al., 2020; Yentrapalli et al., 2013).

References

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

Chang, P. Y. et al. (2017), “MSC-derived cytokines repair radiation-induced intra-villi microvascular injury”, Oncotarget, Vol. 8/50, Impact Journals, Orchard Park, https://doi.org/10.18632/oncotarget.21236

Cheng, Y. P. et al. (2017), “Acid sphingomyelinase/ceramide regulates carotid intima-media thickness in simulated weightless rats”, Pflugers Archiv European Journal of Physiology, Vol. 469, Springer, New York, https://doi.org/10.1007/s00424-017-1969-z

Deanfield, J. et al. (2005), “Endothelial function and dysfunction”, Journal of hypertension, Vol. 23/1, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1097/00004872-200501000-00004

Farhat, N. et al. (2008), “Stress-induced senescence predominates in endothelial cells isolated from atherosclerotic chronic smokers”, Canadian Journal of Physiology and Pharmacology, Vol. 86/11, Canadian Science Publishing, Ottawa, https://doi.org/10.1139/Y08-082

Hughson, R. L., A. Helm and M. Durante (2018), “Heart in space: effect of the extraterrestrial environment on the cardiovascular system”, Nature Reviews Cardiology, Vol. 15/3, Nature Portfolio, London, https://doi.org/10.1038/nrcardio.2017.157

Konukoglu, D., and H. Uzun (2017), “Endothelial Dysfunction and Hypertension”, in Hypertension: from basic research to clinical practice, Springer, London, https://doi.org/10.1007/5584_2016_90

Korpela, E., and S. K. Liu (2014), “Endothelial perturbations and therapeutic strategies in normal tissue radiation damage”, Radiation Oncology, Vol. 9, BioMed Central, London, https://doi.org/10.1186/s13014-014-0266-7

Kressel, M. and P. Groscurth (1994), “Distinction of apoptotic and necrotic cell death by in situ labelling of fragmented DNA”, Cell and Tissue Research, Vol. 278/3, Springer, London, https://doi.org/10.1007/BF00331373

Lee, S. et al.  (2020), “Arterial structure and function during and after long-duration spaceflight”, Journal of Applied Physiology, Vol. 129/1, American Physiological Society, Rockville, https://doi.org/10.1152/japplphysiol.00550.2019

Noren Hooten, N. and M. K. Evans (2017), “Techniques to Induce and Quantify Cellular Senescence”, Journal of Visualized Experiments: JoVE, Vol. 123, MyJove Corporation, Cambridge,  https://doi.org/10.3791/55533

Soucy, K. G. et al. (2011), “HZE 56Fe-ion irradiation induces endothelial dysfunction in rat aorta: Role of xanthine oxidase”, Radiation Research, Vol. 176/4, Radiation Research Society, Bozeman, https://doi.org/10.1667/RR2598.1

Su, Y. T. et al. (2020), “Acid sphingomyelinase/ceramide mediates structural remodeling of cerebral artery and small mesenteric artery in simulated weightless rats”, Life Sciences, Vol. 243, Elsevier, Amsterdam, https://doi.org/10.1016/j.lfs.2019.117253

Verma, S., M. R. Buchanan and T. J. Anderson (2003), “Endothelial function testing as a biomarker of vascular disease”, Circulation, Vol. 108/17, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1161/01.CIR.0000089191.72957.ED

Yano, K. et al. (2007), “Phenotypic heterogeneity is an evolutionarily conserved feature of the endothelium”, Blood, Vol. 109/2, American Society of Hematology, Washington, D.C., https://doi.org/10.1182/blood-2006-05-026401

Yentrapalli, R. et al. (2013), “The PI3K/Akt/mTOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation”, PloS one, Vol. 8/8, PLOS, San Francisco, https://doi.org/10.1371/journal.pone.0070024