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Relationship: 125

Title

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

Impairment, Endothelial network leads to Insufficiency, Vascular

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Impairment, Endothelial network

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Insufficiency, Vascular

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
Disruption of VEGFR Signaling Leading to Developmental Defects	non-adjacent	Moderate	Low	Cataia Ives (send email)	Open for citation & comment	WPHA/WNT Endorsed

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

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

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

An embryo develops normally only with an adequate supply of oxygen, nutrients, molecular signals, and removal of waste products [Maltepe et al. 1997]. In its early stages this may be satisfied by simple diffusion; however, the rate of diffusion becomes limiting beyond a certain mass. The circulatory system becomes functional early in development and is the first organ system to operate in the vertebrate embryo, reflecting this critical role during organogenesis [Chan et al. 2002; Jin et al. 2005; Walls et al. 2008]. With the onset of cardiac function during early organogenesis the primitive vascular system quickly evolves into a patent circulatory system that transports hematopoietic cells through major blood vessels (e.g., dorsal aorta, cardinal veins, and six aortic arches in the branchial region). Impaired endothelial formation impacts this role in many ways through abnormalities in artery/vein development, vascular remodeling, tissue neovascularization, and microvascular ramifications.

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

Biological Plausibility: Problems of insufficient blood support due to slow or weak heartbeat, vessel occlusions, or anemia will take a toll on various organ systems depending on the stage of development and regional responses to oxygen-sensing pathways [Maltepe et al. 1998; Liu et al. 2009; Gerri et al. 2017].

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Empirical Evidence: Microvascular specializations derived from the perineural vascular plexus (PNVP) surrounding the neural tube and choriovitelline system (CVS) in extraembryonic membranes establish critical transport interfaces with the CNS (e.g., blood-brain barrier and retinal vascularization) [Dorrell et al. 2002; Hogan et al. 2004; Bautch and James, 2009; Eichmann and Thomas, 2013; Vissapragada et al. 2014; Fiorentino et al. 2016; Uwamori et al. 2017; Saili et al. 2017; Huang, 2020] and extraembryonic environment [Abbott and Buckalew, 2000; Chen and Zheng, 2014], respectively. These systems are particularly vulnerable to problems of unstable and leaky vessels in otherwise well-defined endothelial networks.

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

Uncertainties and Inconsistencies: Blood flow patterns vary in higher vertebrates as vascular anatomy becomes complicated by asymmetrical loss of some vessels and expansion of others, especially in mammals where prenatal circulatory shunts bypass the fetal lungs and liver due to placental function.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

A number of anti-angiogenic compounds, including Vatalanib and Thalidomide, have been shown to quantitatively impair vascular patterning [Tran et al. 2007; Therapontos et al. 2009; Jang et al. 2009; Rutland et al. 2009; Tal et al. 2014; Vargesson, 2015; Beedie et al. 2016a; Ellis-Hutchings et al. 2017; Kotini et al. 2020]. In exposed zebrafish embryos, early effects of potential vascular disrupting chemicals (pVDCs) invoke changes to the anatomical development of intersegmental vessels from the dorsal aorta [Tal et al. 2014; McCollum et al. 2017]. Thalidomide, for example, has been shown to primarily disrupt immature vascular networks versus more mature vasculature in the embryo [Therapontos et al. 2009; Beedie et al. 2016a, 2016b, 2017]. Evidence for this KER in human studies is indirect, based solely on correlating malformations with vascular anatomy and/or developmental risks for women of reproductive potential or exposed during pregnancy to anti-angiogenic drugs [Husain et al. 2008; van Gelder et al. 2010; Gold et al. 2011; Ligi et al. 2014; Vargesson and Hootnick, 2017]. Key nodes in the ontogenetic regulation of angiogenesis have been investigated with human cell-based high-throughput assay (HTS) platforms in ToxCast to screen for pVDCs acting on the formation, maturation and/or stabilization of endothelial networks [Houck et al. 2009; Knudsen et al. 2011; Kleinstreuer et al. 2014; Saili et al. 2019; Zurlinden et al. 2020]. These studies show the complexity of crosstalk between genetic signals and responses for vascular patterning versus morphoregulatory systems in general.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

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

Mammalian Phenotype Browser (MPO) defines ‘abnormal blood vessel morphology’ (MP:0001614) as “any structural anomaly of the network of tubes that carries blood through the body“. They describe abnormalities linked to: (i) specific cell types of the microvasculature (endothelial cells, pericytes, macrophages); (ii) diversification of arterial, venous, and lymphatic channels; and (iii) organ-specific vascular morphologies including malformations, variations, and pathologies. The subordinate term ‘abnormal vascular development‘ (MP:0000259) defines an “aberrant process of vascular formation“ that neatly captures the biology relevant to this KER. There are 1045 genotypes and 1768 annotations associated with this term (last accessed December 24, 2021).

References

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

Gold NB, Westgate MN, Holmes LB. Anatomic and etiological classification of congenital limb deficiencies. American journal of medical genetics Part A. 2011 Jun;155A(6):1225-35. PubMed PMID: 21557466.

Husain T, Langlois PH, Sever LE, Gambello MJ. Descriptive epidemiologic features shared by birth defects thought to be related to vascular disruption in Texas, 1996-2002. Birth defects research Part A, Clinical and molecular teratology. 2008 Jun;82(6):435-40. PubMed PMID: 18383510.

Kleinstreuer NC, Judson RS, Reif DM, Sipes NS, Singh AV, Chandler KJ, et al. Environmental impact on vascular development predicted by high-throughput screening. Environmental health perspectives. 2011 Nov;119(11):1596-603. PubMed PMID: 21788198. Pubmed Central PMCID: PMC3226499.

Knudsen TB, Kleinstreuer NC. Disruption of embryonic vascular development in predictive toxicology. Birth defects research Part C, Embryo today : reviews. 2011 Dec;93(4):312-23. PubMed PMID: 22271680.

Tal TL, McCollum CW, Harris PS, Olin J, Kleinstreuer N, Wood CE, Hans C, Shah S, Merchant FA, Bondesson M, Knudsen TB, Padilla S and Hemmer MJ. Immediate and long-term consequences of vascular toxicity during zebrafish development. Reproductive Toxicology. 2014;48:51-61.

Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson N. Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation. Proceedings of the National Academy of Sciences of the United States of America. 2009 May 26;106(21):8573-8. PubMed PMID: 19433787. Pubmed Central PMCID: 2688998.

van Gelder MM, van Rooij IA, Miller RK, Zielhuis GA, de Jong-van den Berg LT, Roeleveld N. Teratogenic mechanisms of medical drugs. Human reproduction update. 2010 Jul-Aug;16(4):378-94. PubMed PMID: 20061329.