Aop: 43

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Disruption of VEGFR Signaling Leading to Developmental Defects

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Developmental Vascular Toxicity

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
W1siziisijiwmjavmtivmdevnhlvawt3bzrsc19bt1a0m19mawd1cmuucg5nil0swyjwiiwidgh1bwiilci1mdb4ntawil1d?sha=bdfed4bca5669601

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

USEPA - National Center for Computational Toxicology, Research Triangle Park NC, USA

              LEAD: Tom Knudsen - knudsen.thomas@epa.gov
                    Nancy Baker (Leidos) - baker.nancy@epa.gov
                    Richard Spencer (GDIT) - spencer.richard@epa.gov

Finnish Centre for Alternative Methods, University of Tampere, Tampere Finland

                    Tuula Heinonen - tuula.heinonen@uta.fi 

The Dow Chemical Company, Midland MI, USA

                    Rob Ellis-Hutchings - rellis-hutchings@dow.com 

University of Aberdeen, Aberdeen, Scotland UK

                    Neil Vargesson – n.vargesson@abdn.ac.uk                     

National Toxicology Program/NICEATM-ICCVAM, Research Triangle Park NC, USA

                    Nicole Kleinstreuer – nicole.kleinstreuer@nih.gov

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Cataia Ives   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Tom Knudsen
  • Nancy Baker
  • Cataia Ives

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Open for citation & comment EAGMST Under Review 1.6 Included in OECD Work Plan
This AOP was last modified on July 16, 2022 18:37

Revision dates for related pages

Page Revision Date/Time
Inhibition, VegfR2 January 17, 2022 10:05
Reduction, Angiogenesis January 17, 2022 10:09
Impairment, Endothelial network January 18, 2022 13:21
Insufficiency, Vascular January 18, 2022 12:48
Increased, Developmental Defects January 18, 2022 13:12
Inhibition, VegfR2 leads to Reduction, Angiogenesis January 18, 2022 12:51
Reduction, Angiogenesis leads to Impairment, Endothelial network January 18, 2022 12:54
Impairment, Endothelial network leads to Insufficiency, Vascular January 18, 2022 13:05
Insufficiency, Vascular leads to Increased, Developmental Defects January 18, 2022 13:07
Vatalanib November 29, 2016 18:42
Sunitinib malate Sunitinib (INN) November 29, 2016 18:42

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

BACKGROUND: The cardiovascular system is the first functional organ system to develop in the vertebrate embryo, reflecting its critical role during normal development and pregnancy. Elucidating an AOP for embryonic vascular disruption must consider the stepwise events underlying blood vessel patterning. Vascular development commences in the early embryo with in situ formation of nascent vessels from angioblasts, leading to a primary capillary plexus (vasculogenesis). After the onset of blood circulation, the primary vascular pattern is further expanded as new vessels sprout from pre-existing vessels (angiogenesis). Both processes, vasculogenesis and angiogenesis, are regulated by genetic signals and environmental factors dependent on anatomical region, physiological state, and developmental stage of the embryo. The developing vascular network is further shaped into a hierarchical system of arteries and veins, through progressive effects on blood vessel arborization, branching, and pruning (angioadaptation). These latter influences include hemodynamic forces, regional changes in blood flow, local metabolic demands and growth factor signals. Disruptions in embryonic vascular patterning-adaptation may result in adverse pregnancy outcomes, including birth defects, angiodysplasias and cardiovascular disease, intrauterine growth restriction or prenatal death. Some chemicals may act as potential vascular disrupting compounds (pVDCs) altering the expression, activity or function of molecular signals regulating blood vessel development and remodeling. Critical pathways involve receptor tyrosine kinases (e.g., growth factor-signaling), G-protein coupled receptors (e.g., chemokine signaling), and GPI-anchored receptors (e.g. uPAR system).

DESCRIPTION: This AOP focuses on the regulation and disruption of vasculogenesis-angiogenesis during embryonic development via disruption of the VEGF-signaling pathway. VEGFA binding to its cognate receptor (VEGFR2) triggers angiogenic sprouting, growth and fusion during early development, and in flow-sensing adaptation of vascular development during later development. VEGFR2 inhibition, the postulated molecular initiating event (MIE) for this AOP, may be invoked by effects on VEGFA production, mobility, or receptor binding, and by effects on VEGFR2 cellular expression, molecular function or post-receptor signal transduction pathways. Downstream key events (KE) include altered cell fate and behavior of 'endothelial tip cells' (exploratory behavior, cell migration) and endothelial 'stalk cells' (cell proliferation, apoptosis). KE relationships (KERs) leading to vascular insufficiency then involve local interactions with other cell types (stromal cells, macrophages), the extracellular matrix (ECM) and micro-physiology (hemodynamics, metabolism). Adverse outcomes (AO) would ultimately vary by anatomical region, organ system, gestational stage and state of the embryo, fetus or placenta when an MIE is invoked.

RELEVANCE and APPLICATION: Angiogenesis and vascular disruption is a broad concept. The intended use of this AOP in a regulatory context is the predictive toxicology of developmental hazards, especially for integrating data from high-throughput screening (HTS) assays into cell agent-based models for predicting dysmorphogenesis. As part of an integrated assessment of toxicity, this AOP can identify useful information for assessing adverse outcomes relevant to risk assessment and efficient use of resources for validation through predictive models linking developmental toxicity to vascular disruption. AOP-based computer models that simulate vascular development can usher-in new virtual screening techniques to predict what might happen to a developing embryo when exposed to chemicals across different dose-time-stage scenarios, including the range of effects and how cellular injury propagates across development.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

https://aopwiki.org/wiki/index.php/File:KleinstreuerKnudsenAOPVascularDisruption.jpg

Functionalization of the ToxCast pVDC predictive signature

The ToxCast putative Vascular Disrupting Chemicals (pVDC) signature will be described here and parts will be incorporated into the relevant Key Events sections.

The sectors of the ToxPI are color-represented by features from ToxCast HTS assays indicated by the target of the assays, the characteristics as follows.

Vascular cell adhesion molecule 1 (VCAM1): the pVDC signature aggregates assays from the BioMAP Systems Predictive Toxicology panel [Houck et al., 2009, Kunkel et al., 2004] focusing here on chemical disruption of endothelial VCAM1 expression following stimulation by cytokines-growth factors. This assay endpoint is an in vitro surrogate for inflammatory cell recruitment per endothelial dysfunction and has been probed across five different cell systems: 4H (HUVECs stimulated with IL-4 + histamine); 3C (HUVECs stimulated with IL-1β + TNFα + IFNϒ); CASM3C (primary human coronary artery smooth muscle cells stimulated with IL-1β + TNFα + IFNϒ); LPS (HUVECs co-cultured with monocytes and stimulated with bacterial endotoxin); and hDFCGF (human dermal fibroblasts stimulated with IL-1β + TNFα + IFNϒ and EGF + bFGF + PDGF-BB)[Knudsen and Kleinstreuer, 2011, Kleinstreuer et al., 2014].

Angiogenic cytokines and chemokines: the pVDC signature aggregates features for LPS-induced TNFα protein expression (see BioMAP descriptor above), nuclear factor-kappa B (NFkB) mediated reporter gene activation (Attagene; cis- configuration), and caspase 8 enzymatic activity (NovaScreen; inhibition or activation). TNFα is a proinflammatory cytokine that can promote angiogenesis indirectly through NFkB-mediated expression of angiogenic growth factors, or inhibit angiogenesis by direct effects on endothelial proliferation and survival. The pVDC signature also aggregates features for signaling activity of the pro-angiogenic cytokines interleukin-1 alpha (IL1a, a macrophage-derived activator of TNFα) and interleukin 6 (IL6). These cytokines act through the G-protein coupled receptors (GPCRs) IL1R and IL6R, respectively. CXCL8 (chemokine (C-X-C motif) ligand 8), formerly known as interleukin 8 (IL8), is angiogenic through its cognate GPCRs (CXCR1, CXCR2). In contrast to CXCL8, the chemokines CXCL9 (alias MIG, monokine induced by IFNϒ) and CXCL10 (alias IP10, interferon-inducible cytokine IP-10) are considered anti-angiogenic through their cognate receptor, CXCR3.

Angiogenic growth factors: FGFs and VEGFs exert their effects on endothelial cell proliferation, migration, and differentiation via specific binding to receptor tyrosine kinases VEGFR and FGFR. The pVDC signature has features for liganding VEGFR1, VEGFR2, and VEGFR3 based on receptor kinase activity (RTK, inhibition or activation) from the NovaScreen biochemical profile [Sipes et al. 2013] and for down-regulation of VEGFR2 expression in the 4H BioMAP system (HUVECs stimulated with IL-4 + histamine, B). VEGFR1 is a non-signaling VEGF-A decoy receptor that can be cleaved from the cell surface; VEGFR2 is the most important VEGF-A receptor and a master switch for developmental angiogenesis; and VEGFR3 is a VEGF-C receptor up-regulated by Notch signals. The pVDC signature includes features for the basic helix-loop-helix transcription factors Aryl Hydrocarbon Receptor (AhR) and Hypoxia Inducible Factor-1 alpha (HIF1a) that are upstream regulators of VEGF gene expression during ischemia or hypoxia. HIF1a and AhR are measured in reporter assays (Attagene). In addition to HIF1a and AhR, the pVDC signature has features for the estrogen receptor alpha (ERa), also a trans-activator of VEGF expression. This included human ERa binding activity (NovaScreen), ERa reporter trans-activation (Attagene) and ERE (estrogen responsive element) reporter cis-activation (Attagene).

Angiogenic sprouting: the ephrins (EFNA1 and EFNB2 in particular) couple VEGF signaling to angiogenic sprouting during early development of the embryonic vasculature (vasculogenesis, angiogenesis). The ToxCast pVDC signature included features for EPH-receptor tyrosine kinase biochemical activity (increased or decreased) for receptors EPHA1, EPHA2, EPHB1 and EPHB2 via their cognate cell membrane-anchored ligands (EFNAs). In contrast to the ephrin system, a number of chemicals had activity on diverse assays for urokinase-type plasminogen activator (uPA). That system, consisting of uPA (4 features) and its GPI-anchored receptor, uPAR (8 features) - both assayed in the BioMAP System [Kleinstreuer et al. 2014], functions in VEGFR2-induced changes to focal adhesion and extracellular matrix (ECM) degradation at the leading edge of endothelial cells during angiogenic sprouting. Binding of uPA to uPAR results in serine-protease conversion of plasminogen to plasmin that initiates a proteolytic cascade leading to degradation of the basement membrane and angiogenic sprouting. The uPA proteolytic cascade is suppressed by the serine protease inhibitor, endothelial plasminogen activator inhibitor type 1 (PAI1). The PAI1/uPA/uPAR assays report chemical effects on the system (up or down) across diverse cellular platforms: 4H, 3C, CASM3C, and hDFCGF noted above; BE3C (human bronchial epithelial cells stimulated with IL-1β + TNFα + IFNϒ); and KF3T (human keratinocytes + fibroblasts stimulated with IL-1β + TNFα + IFNϒ + TGF-β). The pVDC signature has features for thrombomodulin (THBD) and the thromboxane A2 (TBXA2) receptor that participate in the regulation of endothelial migration during angiogenic sprouting. THBD is a type I transmembrane glycoprotein that mediates regulator of uPA/uPAR and TBXA2 is an angiogenic eicosanoid generated by endothelial cyclooxygenase-2 (COX-2) following VEGF- or bFGF stimulation. THBD protein expression was monitored in the 3C and CASM3C BioMAP systems (up, down) and TBXA2 was assayed for ligand binding in the NovaScreen platform.

Endothelial cell migration and proliferation: the pVDC signature includes assays for human primary vascular cultures (endothelial and vascular smooth muscle cells). Assays for nuclear localization of beta-catenin (CTNB) are based on the principle that nuclear translocation activates pathways important for endothelial cell migration, proliferation and survival during capillary network formation in HUVEC cells [Muller et al. 2002; Masckauchan et al. 2005].

Vascular stabilization: The signature has features for transforming growth factor-beta 1 (TGF-b), which regulates vascular morphogenesis and integrity, and for Tie2 - a receptor tyrosine kinase activated by the angiopoietins (ANG1, ANG2) that function stabilize nascent vasculature. The pVDC signature has features for the anti-angiogenic phosphatases PTEN (phosphatase and tensin homolog), PTPN11 (tyrosine-protein phosphatase non-receptor type 11) and PTPN12, and endothelial-specific receptor tyrosine protein phosphatase beta (PTPRB). Matrix metalloproteinases (MMPs) 1/2/9 aggregate features on biochemical activity and cellular function of zinc-dependent endopeptidases MMP1, MMP2 and MMP9 that facilitate angiogenesis through ECM degradation by activated endothelial cells.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 305 Inhibition, VegfR2 Inhibition, VegfR2
KE 28 Reduction, Angiogenesis Reduction, Angiogenesis
KE 110 Impairment, Endothelial network Impairment, Endothelial network
KE 298 Insufficiency, Vascular Insufficiency, Vascular
AO 1001 Increased, Developmental Defects Increased, Developmental Defects

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Conception to < Fetal High
Pregnancy High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.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. More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
mouse Mus musculus High NCBI
rats Rattus norvegicus Low NCBI
zebrafish Danio rerio High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

The cardiovascular system is the first organ system to function in the vertebrate embryo, reflecting its critical role during organogenesis [Chan et al. 2002; Jin et al. 2005; Walls et al. 2008]. Blood vessel development commences in the early (sexually undifferentiated) embryo with de novo assembly of angioblasts into a primary capillary plexus (vasculogenesis). With the onset of blood circulation, the primary vascular pattern is further expanded as new vessels sprout from pre-existing vessels (angiogenesis). Both processes, vasculogenesis and angiogenesis, are developmentally regulated by genetic signals and environmental factors dependent on anatomical region, physiological state, and gestational age of the embryo-fetus [Shalaby et al. 1995; Patan, 2000; Jin et al. 2005; Knudsen and Kleinstreuer, 2011; Eberlein et al. 2021]. Disruption of embryonic vascular development is a potential framework for adverse outcome pathways (AOPs) in developmental toxicity [Knudsen and Kleinstreuer, 2011; Kleinstreuer et al. 2013; Saili et al. 2019; Zurlinden et al. 2020]. Developmental angiogenesis is supported by evidence in genetic models of abnormal vascularization leading to severe developmental phenotypes [Fong et al. 1995; Shalaby et al. 1995; Carmeliet et al. 1996; Maltepe et al. 1997; Abbott and Buckalew, 2000; Chan et al. 2002; Coultas et al. 2005; van den Akker et al. 2007; Eberlein et al. 2021]. This may include cell signals and responses driving formation of the primitive capillary network in the early embryo and extraembryonic membranes (vasculogenesis), the subsequent expansion and patterning of the embryonic and placental vasculature (angiogenesis), and its further stabilization, specialization, and remodeling during growth, organogenesis and differentiation. Additional evidence comes from dysmorphogenesis induced with known anti-angiogenic compounds across multiple vertebrate species (e.g., zebrafish, frog, chick, mouse, rat) [Therapontos et al. 2009; Jang et al. 2009; Rutland et al. 2009; Tal et al. 2014; Vargesson, 2015; Beedie et al. 2016; Ellis-Hutchings et al. 2017; Kotini et al. 2020] and human studies of malformations correlated with genetic and/or environmental factors that target vascular development [Husain et al. 2008; Gold et al. 2011; Vargesson and Hootnick, 2017]. An analysis of pharma compounds to which women of reproductive age were exposed identified vascular disruption as one of six potential mechanisms of teratogenesis [van Gelder et al. 2010]. This AOP is focused on disruption of ‘developmental angiogenesis’ from the perspective of dysmorphogenesis leading to severe developmental defects. Although uterine-decidual vascularization is critically important for healthy pregnancy outcomes, the emphasis here is the direct role on anatomical development of the embryo proper.  

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

The Vascular Endothelial Growth Factor (VEGF) pathway is a critical regulatory system for assembly of embryonic blood vessels [Fong et al. 1995; Shalaby et al. 1995; Carmeliet et al. 1996; Ferrara, et al. 1996; Argraves et al. 2002; Hogan et al. 2004; Roberts et al. 2004; Chung and Ferrara, 2011; Shibuya, 2013; Chapell et al. 2016; Jin et al. 2017; Queisser et al. 2021]. The VEGF growth factors belong to the platelet-derived growth factor supergene family. VEGF-A, the major regulator for angiogenesis, binds receptor tyrosine kinases VEGFR-1 (Flt-1) and VEGFR2 (KDR/Flk-1) to regulate endothelial cell proliferation, survival, migration, tubular morphogenesis, and sprouting [Hogan et al. 2004; Douglas et al. 2009; Shibuya, 2013]. This pro-angiogenic effect is locally fashioned as VEGF gradients where the soluble VEGFR1 (sFlt-1) is released from the cell surface as an endogenous VEGF inhibitor that sets up VEGF-A corridors in the developing embryo [Roberts et al. 2004; Chappell et al. 2016]. Genetic studies have shown that perturbing the VEGF signaling system can invoke varying degrees of adverse consequences, ranging from congenital angiodysplasia to fetal malformations and embryolethality [Fong et al. 1995; Ferrara et al. 1996; Eshkar-Oren et al. 2015; Jin et al. 2017]. Filopodial sprouting of the endothelial cell tip (EC-tip) is the critical VEGFR2 responsive cell type specifically in this AOP [Belair et al. 2016a and 2016b]; however, other relevant cell types include: angioblasts (AB) as direct precursors to primary endothelial cells; endothelial ‘stalk’ cells (EC-stalk) proliferate in the wake of an angiogenic sprout; macrophage/microglial cells (MCs) release cytokines, chemokines, and growth factors; and stromal cells (SCs) are recruited to the nascent vascular wall for vessel stabilization. As such, the VEGF gradient/response system influences a multicellular dimension determined by cellular patterns of VEGF expression and processing (eg, MCs, SCs) and biochemical corridors set up by the extracellular matrix and the VEGFR1 decoy receptor (eg, EC-stalk). Evidence supporting an AOP for chemical disruption is available for thalidomide, estrogens, endothelins, dioxin, retinoids, cigarette smoke, and metals among other compounds [Kleinstreuer et al. 2011; Knudsen and Kleinstreuer, 2011; Shirinifard et al. 2013; Tal et al. 2014 and 2017; McCollum et al. 2017; Toimela et al. 2017; Mahony et al. 2018; Saili et al. 2019; Zurlinden et al. 2020]. Although not all compounds with developmental toxicity show an in vitro vascular bioactivity signature, many 'putative vascular disruptor compounds' (pVDCs) invoke adverse developmental consequences [Kleinstreuer et al. 2011 and 2013]. The molecular and cellular biology of human vascular development, stabilization and remodeling is amenable to in vitro assays with human cells [Bishop et al. 1999; Sarkanen et al. 2010; Kleinstreuer et al. 2014; Belair et al. 2016a and 2016b; Nguyen et al. 2017; Toimela et al. 2017; Pauty et al. 2018; van Duinen et al. 2019a and 2019b; Zurlinden et al. 2020], pluripotent stem cells induced to endothelial differentiation [Belair et al. 2015; Sinha and Santoro, 2018; Li et al. 2018; Galaris et al. 2021], and endothelial-specific reporter zebrafish [Tran et al. 2007; Shirinifard et al. 2013; Tal et al. 2014 and 2017; Beedie et al. 2017; McCollum et al. 2017]. An integrated portfolio of assays is thus available to cover many aspects of the angiogenic cycle and its ramifications during neurovascular development [Bautch and James, 2009; Eichman and Thomas, 2013; Saili et al. 2017; Uwamori et al. 2017; van Duinen et al. 2019; and Zurlinden et al. 2020]. Evidence is also available to support the essentiality of this AOP outside the embryo proper, such as uterine angiogenesis [Douglas et al. 2009; Araujo et al. 2021], placentation [Abbott and Bucklew, 2000; Chen and Zheng, 2014], and human pregnancies complicated by preeclampsia and small-for-gestational age infants [Andraweera et al. 2012].

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Weight of evidence for the MIE and AO are strong; the intermediate KEs have in some cases strong evidence but in other cases weaker evidence, due to the lack of quantitative information. the KERs are biologically plausible. Several manuscripts have been published recently that bolster weight of evidence [Belair et al. 2016; Nguyen et al. 2017; Tal et al. 2017; McCollum et al. 2017; Ellis-Hutchings et al. 2017; Saili et al. 2019; Zurlinden et al. 2020].

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

 

AOP ZFE.jpg

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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

 

Abbott, B. D. and A. R. Buckalew (2000). Placental defects in ARNT-knockout conceptus correlate with localized decreases in VEGF-R2, Ang-1, and Tie-2. Developmental dynamics : an official publication of the American Association of Anatomists 219(4): 526-5384. PMID: 11084652.

Andraweera, P. H., G. A. Dekker, S. D. Thompson and C. T. Roberts (2012). Single-nucleotide polymorphisms in the KDR gene in pregnancies complicated by gestational hypertensive disorders and small-for-gestational-age infants. Reproductive sciences (Thousand Oaks, Calif.) 19(5): 547-5545. PMID: 22344734.

Araujo Júnior, E., A. C. Zamarian, A. C. Caetano, et al. (2021). Physiopathology of late-onset fetal growth restriction. Minerva obstetrics and gynecology 73(4): 392-4084. PMID: 33876907.

Argraves, W. S., A. C. Larue, P. A. Fleming and C. J. Drake (2002). VEGF signaling is required for the assembly but not the maintenance of embryonic blood vessels. Developmental dynamics : an official publication of the American Association of Anatomists 225(3): 298-3043. PMID: 12412012.

Bautch, V. L. and J. M. James (2009). Neurovascular development: The beginning of a beautiful friendship. Cell adhesion & migration 3(2): 199-2042. PMID: 19363295.

Beedie, S. L., A. J. Diamond, L. R. Fraga, et al. (2017). Vertebrate embryos as tools for anti-angiogenic drug screening and function. Reproductive toxicology (Elmsford, N.Y.) 70: 49-59. PMID: 27888069.

Beedie, S. L., C. Mahony, H. M. Walker, et al. (2016). Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model. Scientific reports 6: 30038-30038. PMID: 27443489.

Belair, D. G., M. J. Miller, S. Wang, et al. (2016). Differential regulation of angiogenesis using degradable VEGF-binding microspheres. Biomaterials 93: 27-37. PMID: 27061268.

Belair, D. G., M. P. Schwartz, T. Knudsen and W. L. Murphy (2016). Human iPSC-derived endothelial cell sprouting assay in synthetic hydrogel arrays. Acta biomaterialia 39: 44554-44554. PMID: 27181878.

Belair, D. G., J. A. Whisler, J. Valdez, et al. (2015). Human vascular tissue models formed from human induced pluripotent stem cell derived endothelial cells. Stem cell reviews and reports 11(3): 511-5253. PMID: 25190668.

Bishop, E. T., G. T. Bell, S. Bloor, et al. (1999). An in vitro model of angiogenesis: basic features. Angiogenesis 3(4): 335-3444. PMID: 14517413.

Carmeliet, P., V. Ferreira, G. Breier, et al. (1996). Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380(6573): 435-4396573. PMID: 8602241.

Chan, J., P. E. Bayliss, J. M. Wood and T. M. Roberts (2002). Dissection of angiogenic signaling in zebrafish using a chemical genetic approach. Cancer cell 1(3): 257-2673. PMID: 12086862.

Chappell, J. C., J. G. Cluceru, J. E. Nesmith, et al. (2016). Flt-1 (VEGFR-1) coordinates discrete stages of blood vessel formation. Cardiovascular research 111(1): 84-931. PMID: 27142980.

Chen, D. B. and J. Zheng (2014). Regulation of placental angiogenesis. Microcirculation (New York, N.Y. : 1994) 21(1): 15-251. PMID: 23981199.

Chung, A. S. and N. Ferrara (2011). Developmental and pathological angiogenesis. Annual review of cell and developmental biology 27: 563-584. PMID: 21756109.

Coultas, L., K. Chawengsaksophak and J. Rossant (2005). Endothelial cells and VEGF in vascular development. Nature 438(7070): 937-9457070. PMID: 16355211.

Douglas, N. C., H. Tang, R. Gomez, et al. (2009). Vascular endothelial growth factor receptor 2 (VEGFR-2) functions to promote uterine decidual angiogenesis during early pregnancy in the mouse. Endocrinology 150(8): 3845-38548. PMID: 19406950.

Eberlein, J., L. Herdt, J. Malchow, et al. (2021). Molecular and Cellular Mechanisms of Vascular Development in Zebrafish. Life (Basel, Switzerland) 11(10)10. PMID: 34685459.

Eichmann, A. and J. L. Thomas (2013). Molecular parallels between neural and vascular development. Cold Spring Harbor perspectives in medicine 3(1): a006551-a0065511. PMID: 23024177.

Ellis-Hutchings, R. G., R. S. Settivari, A. T. McCoy, et al. (2017). Embryonic vascular disruption adverse outcomes: Linking high throughput signaling signatures with functional consequences. Reproductive toxicology (Elmsford, N.Y.) 70: 82-96. PMID: 28527947.

Eshkar-Oren, I., S. Krief, N. Ferrara, et al. (2015). Vascular patterning regulates interdigital cell death by a ROS-mediated mechanism. Development (Cambridge, England) 142(4): 672-6804. PMID: 25617432.

Ferrara, N., K. Carver-Moore, H. Chen, et al. (1996). Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380(6573): 439-4426573. PMID: 8602242.

Fong, G. H., J. Rossant, M. Gertsenstein and M. L. Breitman (1995). Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376(6535): 66-706535. PMID: 7596436.

Galaris, G., J. H. Thalgott, E. Teston and F. P. G. Lebrin (2021). In vitro Three-Dimensional Sprouting Assay of Angiogenesis using Mouse Embryonic Stem Cells for Vascular Disease Modeling and Drug Testing. Journal of visualized experiments : JoVE(171)171. PMID: 34057453.

Gold, N. B., M. N. Westgate and L. B. Holmes (2011). Anatomic and etiological classification of congenital limb deficiencies. American journal of medical genetics. Part A 155A(6): 1225-12356. PMID: 21557466.

Hogan, K. A., C. A. Ambler, D. L. Chapman and V. L. Bautch (2004). The neural tube patterns vessels developmentally using the VEGF signaling pathway. Development (Cambridge, England) 131(7): 1503-15137. PMID: 14998923.

Husain, T., P. H. Langlois, L. E. Sever and M. J. Gambello (2008). 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 82(6): 435-4406. PMID: 18383510.

Jang, G. H., I. S. Park, S. H. Lee, et al. (2009). Malachite green induces cardiovascular defects in developing zebrafish (Danio rerio) embryos by blocking VEGFR-2 signaling. Biochemical and biophysical research communications 382(3): 486-4913. PMID: 19364469.

Jin, D., D. Zhu, Y. Fang, et al. (2017). Vegfa signaling regulates diverse artery/vein formation in vertebrate vasculatures. Journal of genetics and genomics = Yi chuan xue bao 44(10): 483-49210. PMID: 29037991.

Jin, S. W., D. Beis, T. Mitchell, et al. (2005). Cellular and molecular analyses of vascular tube and lumen formation in zebrafish. Development (Cambridge, England) 132(23): 5199-520923. PMID: 16251212.

Kleinstreuer, N., D. Dix, M. Rountree, et al. (2013). A computational model predicting disruption of blood vessel development. PLoS computational biology 9(4): e1002996-e10029964. PMID: 23592958.

Kleinstreuer, N. C., R. S. Judson, D. M. Reif, et al. (2011). Environmental impact on vascular development predicted by high-throughput screening. Environmental health perspectives 119(11): 1596-160311. PMID: 21788198.

Kleinstreuer, N. C., J. Yang, E. L. Berg, et al. (2014). Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms. Nature biotechnology 32(6): 583-5916. PMID: 24837663.

Knudsen, T. B. and N. C. Kleinstreuer (2011). Disruption of embryonic vascular development in predictive toxicology. Birth defects research. Part C, Embryo today : reviews 93(4): 312-3234. PMID: 22271680.

Kotini, M. P., F. Bachmann, J. Spickermann, et al. (2020). Probing the Effects of the FGFR-Inhibitor Derazantinib on Vascular Development in Zebrafish Embryos. Pharmaceuticals (Basel, Switzerland) 14(1)1. PMID: 33396726.

Li, S., C. W. Hsu, S. Sakamuru, et al. (2018). Identification of Angiogenesis Inhibitors Using a Co-culture Cell Model in a High-Content and High-Throughput Screening Platform. SLAS technology 23(3): 217-2253. PMID: 28922619.

Mahony, C., S. McMenemy, A. J. Rafipay, et al. (2018). CPS49-induced neurotoxicity does not cause limb patterning anomalies in developing chicken embryos. Journal of anatomy 232(4): 568-5744. PMID: 29023763.

Maltepe, E., J. V. Schmidt, D. Baunoch, et al. (1997). Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature 386(6623): 403-4076623. PMID: 9121557.

McCollum, C. W., J. Conde-Vancells, C. Hans, et al. (2017). Identification of vascular disruptor compounds by analysis in zebrafish embryos and mouse embryonic endothelial cells. Reproductive toxicology (Elmsford, N.Y.) 70: 60-69. PMID: 27838387.

Nguyen, E. H., W. T. Daly, N. N. T. Le, et al. (2017). Versatile synthetic alternatives to Matrigel for vascular toxicity screening and stem cell expansion. Nature biomedical engineering 1. PMID: 29104816.

Patan, S. (2000). Vasculogenesis and angiogenesis as mechanisms of vascular network formation, growth and remodeling. Journal of neuro-oncology 50(44198): 44211-4421144198. PMID: 11245270.

Pauty, J., R. Usuba, I. G. Cheng, et al. (2018). A Vascular Endothelial Growth Factor-Dependent Sprouting Angiogenesis Assay Based on an In Vitro Human Blood Vessel Model for the Study of Anti-Angiogenic Drugs. EBioMedicine 27: 225-236. PMID: 29289530.

Queisser, A., E. Seront, L. M. Boon and M. Vikkula (2021). Genetic Basis and Therapies for Vascular Anomalies. Circulation research 129(1): 155-1731. PMID: 34166070.

Roberts, D. M., J. B. Kearney, J. H. Johnson, et al. (2004). The vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR-1) modulates Flk-1 (VEGFR-2) signaling during blood vessel formation. The American journal of pathology 164(5): 1531-15355. PMID: 15111299.

Rutland, C. S., K. Jiang, G. A. Soff and C. A. Mitchell (2009). Maternal administration of anti-angiogenic agents, TNP-470 and Angiostatin4.5, induces fetal microphthalmia. Molecular vision 15: 1260-1269. PMID: 19572040.

Saili, K. S., J. A. Franzosa, N. C. Baker, et al. (2019). Systems Modeling of Developmental Vascular Toxicity. Current opinion in toxicology 15(1): 55-631. PMID: 32030360.

Saili, K. S., T. J. Zurlinden, A. J. Schwab, et al. (2017). Blood-brain barrier development: Systems modeling and predictive toxicology. Birth defects research 109(20): 1680-171020. PMID: 29251840.

Sarkanen, J. R., M. Mannerström, H. Vuorenpää, et al. (2010). Intra-Laboratory Pre-Validation of a Human Cell Based in vitro Angiogenesis Assay for Testing Angiogenesis Modulators. Frontiers in pharmacology 1: 147-147. PMID: 21779245.

Shalaby, F., J. Rossant, T. P. Yamaguchi, et al. (1995). Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376(6535): 62-666535. PMID: 7596435.

Shibuya, M. (2013). Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. Journal of biochemistry 153(1): 13-191. PMID: 23172303.

Shirinifard, A., C. W. McCollum, M. B. Bolin, et al. (2013). 3D quantitative analyses of angiogenic sprout growth dynamics. Developmental dynamics : an official publication of the American Association of Anatomists 242(5): 518-5265. PMID: 23417958.

Sinha, S. and M. M. Santoro (2018). New models to study vascular mural cell embryonic origin: implications in vascular diseases. Cardiovascular research 114(4): 481-4914. PMID: 29385541.

Tal, T., C. Kilty, A. Smith, et al. (2017). Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model for developmental vascular toxicity. Reproductive toxicology (Elmsford, N.Y.) 70: 70-81. PMID: 28007540.

Tal, T. L., C. W. McCollum, P. S. Harris, et al. (2014). Immediate and long-term consequences of vascular toxicity during zebrafish development. Reproductive toxicology (Elmsford, N.Y.) 48: 51-61. PMID: 24907688.

Therapontos, C., L. Erskine, E. R. Gardner, et al. (2009). 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 106(21): 8573-857821. PMID: 19433787.

Toimela, T., O. Huttala, E. Sabell, et al. (2017). Intra-laboratory validated human cell-based in vitro vasculogenesis/angiogenesis test with serum-free medium. Reproductive toxicology (Elmsford, N.Y.) 70: 116-125. PMID: 27915012.

Tran, T. C., B. Sneed, J. Haider, et al. (2007). Automated, quantitative screening assay for antiangiogenic compounds using transgenic zebrafish. Cancer research 67(23): 11386-1139223. PMID: 18056466.

Uwamori, H., T. Higuchi, K. Arai and R. Sudo (2017). Integration of neurogenesis and angiogenesis models for constructing a neurovascular tissue. Scientific reports 7(1): 17349-173491. PMID: 29229920.

van den Akker, N. M., D. G. Molin, P. P. Peters, et al. (2007). Tetralogy of fallot and alterations in vascular endothelial growth factor-A signaling and notch signaling in mouse embryos solely expressing the VEGF120 isoform. Circulation research 100(6): 842-8496. PMID: 17332426.

van Duinen, V., W. Stam, V. Borgdorff, et al. (2019). Standardized and Scalable Assay to Study Perfused 3D Angiogenic Sprouting of iPSC-derived Endothelial Cells In Vitro. Journal of visualized experiments : JoVE(153)153. PMID: 31762444.

van Duinen, V., D. Zhu, C. Ramakers, et al. (2019). Perfused 3D angiogenic sprouting in a high-throughput in vitro platform. Angiogenesis 22(1): 157-1651. PMID: 30171498.

van Gelder, M. M., I. A. van Rooij, R. K. Miller, et al. (2010). Teratogenic mechanisms of medical drugs. Human reproduction update 16(4): 378-3944. PMID: 20061329.

Vargesson, N. (2015). Thalidomide-induced teratogenesis: history and mechanisms. Birth defects research. Part C, Embryo today : reviews 105(2): 140-1562. PMID: 26043938.

Vargesson, N. and D. R. Hootnick (2017). Arterial dysgenesis and limb defects: Clinical and experimental examples. Reproductive toxicology (Elmsford, N.Y.) 70: 21-29. PMID: 27773741.

Walls, J. R., L. Coultas, J. Rossant and R. M. Henkelman (2008). Three-dimensional analysis of vascular development in the mouse embryo. PloS one 3(8): e2853-e28538. PMID: 18682734.

Zurlinden, T. J., K. S. Saili, N. C. Baker, et al. (2020). A cross-platform approach to characterize and screen potential neurovascular unit toxicants. Reproductive toxicology (Elmsford, N.Y.) 96: 300-315. PMID: 32590145.