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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

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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	Cataia Ives (send email)	Open for citation & comment

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. As the layer separating blood and vessel walls, the endothelium controls the flow of molecules, fluid, and circulating blood cells between the two. However, the specific functions and even the structure of endothelial cells vary greatly depending on the organ (Ricard et al., 2021). Dysfunction to the vascular endothelium can age arteries and is the result of increased proliferation and apoptotic behaviour of cells including an increased response to endothelial constrictors. It is also represented by an imbalance between vasodilators and vasoconstrictors which are produced by the endothelium. The dysfunction can encompass vasospasm, thrombosis, penetration of immune cells (i.e macrophage) and an increase in cyclooxygenase. These processes can activate the endothelium and a prolonged state of activation is problematic and is referred to as endothelial dysfunction (Sitia et al., 2010; Deanfield et al., 2005; Konukoglu & Uzun, 2017; Korpela & Liu, 2014). Other factors leading to endothelial dysfunction are loss in endothelial function leading to cell senescence and a low proliferative capacity of endothelial progenitor cells.

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

Endothelial cell senescence

Assay	Reference	Description	OECD Approved Assay
Senescence-associated beta-galactosidase staining (SA-beta-gal)	(Farhat et al., 2008; González-Gualda et al., 2021; Hooten et al., 2017)	Can be used to measure senescence-associated β-galactosidase activity, a marker for senescent cells.	No
Bromodeoxyuridine (BrdU) detected with staining incorporation	(González-Gualda et al., 2021)	Reduced BrdU incorporation can indicate a lack of DNA synthesis.	No
Immunohistochemistry to detect senescence markers.	(González-Gualda et al., 2021)	Markers include Ki67 and Lamin B1. Reduced Ki67 can indicate reduced proliferation. Reduced Lamin B1 indicates impaired structural integrity of the nucleus.	No
Cell morphology and size measured with light microscopy or flow cytometry.	(González-Gualda et al., 2021)	Senescent cells exhibit an enlarged and flattened morphology.	No

Cell death:

See the increase, cell death KE for methods to measure endothelial cell death.

Impaired vasomotion

Assay	Reference	Description	OECD Approved Assay
Concentration-response curves to vasodilators/vasoconstrictors	(Deanfield et al., 2005; Verma 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
Detection of contractile factors (eg. endothelin) using enzyme-linked immunosorbent assay (ELISA).	(Abdel-Sayed et al., 2003)	Endothelin is an endothelium-derived vasoconstrictor.	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: Although endothelial dysfunction may occur due to aging (Hererra et al., 2010), this key event can occur at any life stage (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

Abdel-Sayed, S. et al. (2003), “Measurement of plasma endothelin-1 in experimental hypertension and in healthy subjects”, American Journal of Hypertension, Vol. 16/7, Oxford University Press, Oxford, https://doi.org/10.1016/S0895-7061(03)00903-8

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

González-Gualda, E. et al. (2021), “A guide to assessing cellular senescence in vitro and in vivo”, The FEBS Journal, Vol. 288, FEBS press, https://doi.org/10.1111/febs.15570

Herrera, M. D. et al. (2010), “Endothelial dysfunction and aging: An update”, Ageing Research Reviews, Vol 9/2, Elsevier, Amsterdam, https://doi.org/10.1016/j.arr.2009.07.002

Hooten, N. 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

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

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

Ricard, N. et al. (2021), “The quiescent endothelium: signalling pathways regulating organ-specific endothelial normalcy”, Nature reviews cardiology, Vol. 18/8, Springer Nature, https://doi.org/10.1038/s41569-021-00517-4

Sitia, S. et al. (2010), “From endothelial dysfunction to atherosclerosis”, Autoimmunity Reviews, Vol. 9/12, Elsevier, Amsterdam, https://doi.org/10.1016/j.autrev.2010.07.016

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