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Event: 298

Key Event Title

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

Insufficiency, Vascular

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
Insufficiency, Vascular
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Biological Context

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Level of Biological Organization
Molecular

Cell 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

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
embryo

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
Process Object Action
blood circulation blood decreased
capillary plexus abnormal

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
Developmental Vascular Toxicity KeyEvent Tom Knudsen (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 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

Life Stages

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

Sex Applicability

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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

Embryonic blood vessels form in a reproducible pattern that interfaces with other embryonic structures and tissues [Hogan et al. 2004]. Many human diseases, including stroke, retinopathy, and cancer, are associated with the vascular biology, including endothelial cells and pericytes that establish the blood-brain barrier and control cerebrovascular exchanges [Bautch and James, 2009; Eichmann and Thomas, 2013; Saili et al. 2017]. Functionally, blood vessel morphogenesis is critical for providing oxygen, nutrients and molecular signals to developing tissues [Maltepe et al. 1997; Vargesson, 2003; Chung and Ferrara, 2011; Eshkar-Oren et al. 2015]. The developing vascular network is shaped into a hierarchical system of arteries and veins, through progressive effects on blood vessel arborization (microvasculature) and pruning (angio-adaptation) [Jin et al. 2017]. The former is morpho-regulatory whereas the reshaping is influenced by regional changes in blood flow and local metabolic demands [Tran et al. 2007]. Evidence supports the ability of physiological parameters such as oxygen and glucose concentrations to affect the expression of genes critical for developmental angiogenesis [Maltepe and Simon, 1998]. Growth in tissue mass during organogenesis is thought to lead to the formation of hypoxic/nutrient-deprived cells. The subsequent activation of sensors such as HIF-1 [Xia et al. 2009; Oladipupo et al. 2011; Li et al. 2018] and ARNT [Maltepe et al. 1997; Abbott and Buckalew, 2000] that rapidly trans-activate the expression of genes such as VEGF that drive angiogenesis.

While mammalian embryos become sensitive to hypoxia during early organogenesis, the small size of zebrafish embryos renders this species less vulnerable to hypoxia than vertebrate counterparts; however, the genetic control of microvascular development is conserved among vertebrate species as evidenced by hypoxia-responsive signaling (HIF-1) via local oxygen-sensing gradients in the zebrafish, chick and mouse embryo [Hogan et al. 2004; Liu et al. 2017; Gerri et al. 2017]. The neural tube, for example, provides vascular patterning signals that direct formation of the perineural vascular plexus (PNVP) that encompasses the neural tube at mid-gestation [Hogan et al. 2004]. This process is temporally and spatially associated with Vegfa expression as the neural tube signal through VEGFR-2. Mesodermal VEGFR-2 expression is localized to the lateral portion of the somite and later to sclerotomal cells surrounding the neural tube under the positive control of BMP4 signaling and negative control by Noggin, a BMP4 antagonist [Nimmagadda et al. 2005]. Reciprocal signaling between VEGF-induced endothelial cells and neuroprogenitor cells enhanced formation of the brain neurovascular unit [Vissapragada et al. 2014]. In transgenic zebrafish embryos, the VEGFR-2 antagonist, Vatalanib produced a direct concentration-dependent progression of impaired intersegmental vessel (ISV) outgrowth in early embryos, increased rates of malformed hatched larva, and reduced survival in juvenile cohorts [Tal et al. 2014]. These data show that disruption in the early embryo has a lasting impact on advanced life stages.

Another key cell sensing activity is the recruitment of macrophage (microglia?) cells that secrete pro-angiogenic cytokines and proteases, remodeling the extracellular matrix (ECM) and providing survival and guidance cues to endothelial cells [Gerri et al. 2017]. Macrophages play crucial roles at each step of the angiogenic cycle, from sprouting to maturation and remodelling of the vascular plexus through angiopoietin-TIE2 signaling [Du Cheyne et al. 2020], which is known to synergize with the VEGF-pathway during developmental angiogenesis [Li et al. 2014]. A seminal study showed that loss of immature blood vessels is the primary cause of Thalidomide-induced teratogenesis in the chick embryo, where anti-angiogenic but not anti-inflammatory analogues of Thalidomide induced limb reduction defects. Outgrowth and remodeling of more mature blood vessels delayed, whereas newly formed angiogenic vessels were lost prior to limb dysmorphogenesis and altered patterns of gene expression [Therapontos et al. 2009; Vargesson, 2015]. Vascular insufficiency is likely important in human embryos where the window of vulnerability to Thalidomide-induced phocomelia precedes full establishment of the adult arterial pattern by the 8th week of gestation [Hootnick et al. 2016; Hootnick et al. 2017; Vargesson and Hootnick, 2017].

As such, a chemical’s potential to disrupt vascular patterning and/or remodeling during organogenesis can have profound effects on many systems, including: early limb development [Beedie et al. 2016a, 2016b, 2017 and 2020]; neurovascular development [Hogan et al. 2004; Hallene et al. 2006; Bautch and James, 2009; Eichman and Thomas, 2013; Vissapragada et al. 2014;  Fiorentino et al. 2016; Uwamori et al. 2017; Huang, 2020]; and utero-placental development [Abbott and Buckalew, 2000; Douglas et al. 2009; Rutland et al. 2009; Chen, 2014; Araujo et al. 2021].

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

Complex functional assays such as the rat aortic explant assay, rat whole embryo culture, and the zebrafish embryotoxicity along with transcriptomic signatures provide a tiered approach to evaluate HTS signatures and their taxonomic implications for conserved pathways to prioritize further in vivo testing studies [Ellis-Hutchings et al. 2017].

Zebrafish reporter assays: Blood flow begins in the zebrafish embryo at 24 h postfertilization. Shortly after this, the angiogenic vessels that perfuse the trunk of the embryo (intersegmental vessels) sprout from the vasculogenic vessels [Tran et al. 2007]. These effects can be visualized in automated, quantitative screening assays using transgenic zebrafish expressing green fluorescent protein (GFP) under the control of the vascular endothelial growth factor receptor (VEGFR) Vegfr2 promoter that restricts reporter gene expression to developing blood vessels. Phenotypic readouts have been used to screen and validate anti-angiogenic compounds [Tran et al. 2007; Yano et al. 2012; Yozzo et al. 2013; Tal et al. 2014; McCollum et al. 2017]. Live-cell imaging has been used to quantitatively detect the trajectory dynamics of vascular patterning [Clendenon et al. 2013; Shirinfard et al. 2013] and confocal cell imaging has been used to develop a quantitative assay capable of detecting relatively subtle changes (~8%) in relative to controls during chemical exposure [Tal et al. 2017].

ToxCast: A study evaluated two anti-angiogenic agents, 5HPP-33, a synthetic Thalidomide analog [Noguchi et al. 2005] and TNP-470, a synthetic Fumagillan analog [Ingber et al. 1990] across the ToxCast HTS assay platform and anchored the results to complex in vitro functional assays: the rat aortic explant assay, rat whole embryo culture, and zebrafish embryotoxicity [Saili et al. 2019]. Both compounds disrupted angiogenesis and embryogenesis in the functional assays, with differences in potency and adverse effects. 5HPP-33 was embryolethal, whereas TNP-470 produced caudal defects at low concentrations [Ellis-Hutchings et al. 2017]. Anti-angiogenic modes of action are known for 5HPP-33, which blocks tubulin polymerization inhibition [Yeh et al. 2000; Inatsuki et al. 2005; Kizaki et al. 2008; Rashid et al. 2015); and TNP-470, a methionine aminopeptidase II (MetAP2) inhibition, through non-canonical Wnt inhibition of endothelial proliferation [Ingber et al. 1990]. Transcriptomic profiles of exposed embryos pathways unique to each and in common to both, strongest being the TP53 pathway [Saili et al. 2019]. In mouse, TNP-470 reduced fetal intraocular microvasculature and induced microphthalmia, either directly or via effects on placental morphology [Rutland et al. 2009].

Computational models: Critical pathways for developmental angiogenesis and potential disruptions have critical signal-response systems embedded in three types of receptors that play key roles in a number of morphoregulatory processes: receptor tyrosine kinases (e.g., growth factor-signaling), G-protein coupled receptors (e.g., chemokine signaling), and GPI-anchored receptors (e.g., uPAR system). Computational approaches have been used to predict vascular insufficiency for potential vascular disrupting chemicals (pVDCs) that are developmental toxicants or non-toxicants [Kleinstreuer et al. 2011; Knudsen and Kleinstreuer, 2011]. This has been applied to the ToxCast inventory to rank order over a thousand chemicals for validation testing [McCollum et al. 2017; Tal et al. 2017; Saili et al. 2019; Zurlinden et al. 2020].

Domain of Applicability

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

Complex functional assays such as the rat aortic explant assay (AEA), rat whole embryo culture (WEC), and the zebrafish embryotoxicity (ZET) along with transcriptomic signatures provide a tiered approach to evaluate HTS signatures and their taxonomic implications for conserved pathways to prioritize further in vivo testing studies [Ellis-Hutchings et al. 2017].

References

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

Abbott, B. D. and Buckalew, A. R. (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, 526-538. doi:10.1002/1097-0177(2000)9999:9999<::AID-DVDY1080>3.0.CO;2-N. PMID:11084652

Araujo Júnior, E., Zamarian, A. C., Caetano, A. C. et al. (2021). Physiopathology of late-onset fetal growth restriction. Minerva obstetrics and gynecology 73, 392-408. doi:10.23736/S2724-606X.21.04771-7. PMID:33876907

Bautch, V. L. and James, J. M. (2009). Neurovascular development: The beginning of a beautiful friendship. Cell adhesion & migration 3, 199-204. doi:10.4161/cam.3.2.8397. PMID:19363295

Beedie, S. L., Mahony, C., Walker, H. M. et al. (2016). Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model. Scientific reports 6, 30038-30038. doi:10.1038/srep30038. PMID:27443489

Beedie, S. L., Rore, H. M., Barnett, S. et al. (2016). In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems. Oncotarget 7, 33237-33245. doi:10.18632/oncotarget.8909. PMID:27120781

Beedie, S. L., Diamond, A. J., Fraga, L. R. et al. (2017). Vertebrate embryos as tools for anti-angiogenic drug screening and function. Reproductive toxicology (Elmsford, N.Y.) 70, 49-59. doi:10.1016/j.reprotox.2016.11.013. PMID:27888069

Beedie, S. L., Huang, P. A., Harris, E. M. et al. (2020). Role of cereblon in angiogenesis and in mediating the antiangiogenic activity of immunomodulatory drugs. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34, 11395-11404. doi:10.1096/fj.201903060RR. PMID:32677118

Chen, D. B. and Zheng, J. (2014). Regulation of placental angiogenesis. Microcirculation (New York, N.Y. : 1994) 21, 15-25. doi:10.1111/micc.12093. PMID:23981199

Chung, A. S. and Ferrara, N. (2011). Developmental and pathological angiogenesis. Annual review of cell and developmental biology 27, 563-584. doi:10.1146/annurev-cellbio-092910-154002. PMID:21756109

Douglas, N. C., Tang, H., Gomez, R. 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, 3845-3854. doi:10.1210/en.2008-1207. PMID:19406950

Du Cheyne, C., Tay, H. and De Spiegelaere, W. (2020). The complex tie between macrophages and angiogenesis. Anatomia, histologia, embryologia 49, 585-596. doi:10.1111/ahe.12518. PMID:31774212

Eichmann, A. and Thomas, J. L. (2013). Molecular parallels between neural and vascular development. Cold Spring Harbor perspectives in medicine 3, a006551-a006551. doi:10.1101/cshperspect.a006551. PMID:23024177

Ellis-Hutchings, R. G., Settivari, R. S., McCoy, A. T. et al. (2017). Embryonic vascular disruption adverse outcomes: Linking high throughput signaling signatures with functional consequences. Reproductive toxicology (Elmsford, N.Y.) 70, 82-96. doi:10.1016/j.reprotox.2017.05.005. PMID:28527947

Eshkar-Oren, I., Krief, S., Ferrara, N. et al. (2015). Vascular patterning regulates interdigital cell death by a ros-mediated mechanism. Development (Cambridge, England) 142, 672-680. doi:10.1242/dev.120279. PMID:25617432

Fiorentino, M., Sapone, A., Senger, S. et al. (2016). Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Molecular autism 7, 49-49. doi:10.1186/s13229-016-0110-z. PMID:27957319

Gerri, C., Marín-Juez, R., Marass, M. et al. (2017). Hif-1a regulates macrophage-endothelial interactions during blood vessel development in zebrafish. Nature communications 8, 15492-15492. doi:10.1038/ncomms15492. PMID:28524872

Hallene, K. L., Oby, E., Lee, B. J. et al. (2006). Prenatal exposure to thalidomide, altered vasculogenesis, and cns malformations. Neuroscience 142, 267-283. doi:10.1016/j.neuroscience.2006.06.017. PMID:16859833

Hogan, K. A., Ambler, C. A., Chapman, D. L. et al. (2004). The neural tube patterns vessels developmentally using the vegf signaling pathway. Development (Cambridge, England) 131, 1503-1513. doi:10.1242/dev.01039. PMID:14998923

Hootnick, D. R., DeSesso, J. M. and Vargesson, N. (2016). Congenital embryonic arterial and skeletal dysgeneses. Radiographics : a review publication of the Radiological Society of North America, Inc 36, 1257-1257. doi:10.1148/rg.2016150243. PMID:27399246

Hootnick, D. R., Vargesson, N. and Birch, J. (2017). Regarding a limb with pffd, fibular dimelia and mirror foot deformity. Journal of pediatric orthopedics. Part B 26, 589-589. doi:10.1097/BPB.0000000000000490. PMID:28945698

Huang, H. (2020). Pericyte-endothelial interactions in the retinal microvasculature. International journal of molecular sciences 21, doi:10.3390/ijms21197413. PMID:33049983

Inatsuki, S., Noguchi, T., Miyachi, H. et al. (2005). Tubulin-polymerization inhibitors derived from thalidomide. Bioorganic & medicinal chemistry letters 15, 321-325. doi:10.1016/j.bmcl.2004.10.072. PMID:15603947

Ingber, D., Fujita, T., Kishimoto, S. et al. (1990). Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 348, 555-557. doi:10.1038/348555a0. PMID:1701033

Jin, D., Zhu, D., Fang, Y. et al. (2017). Vegfa signaling regulates diverse artery/vein formation in vertebrate vasculatures. Journal of genetics and genomics = Yi chuan xue bao 44, 483-492. doi:10.1016/j.jgg.2017.07.005. PMID:29037991

Kizaki, M. and Hashimoto, Y. (2008). New tubulin polymerization inhibitor derived from thalidomide: Implications for anti-myeloma therapy. Current medicinal chemistry 15, 754-765. doi:10.2174/092986708783955473. PMID:18393844

Kleinstreuer, N. C., Judson, R. S., Reif, D. M. et al. (2011). Environmental impact on vascular development predicted by high-throughput screening. Environmental health perspectives 119, 1596-1603. doi:10.1289/ehp.1103412. PMID:21788198

Knudsen, T. B. and Kleinstreuer, N. C. (2011). Disruption of embryonic vascular development in predictive toxicology. Birth defects research. Part C, Embryo today : reviews 93, 312-323. doi:10.1002/bdrc.20223. PMID:22271680

Li, S., Hsu, C. W., Sakamuru, S. 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, 217-225. doi:10.1177/2472630317729792. PMID:28922619

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Liu, H., Yang, Q., Radhakrishnan, K. et al. (2009). Role of vegf and tissue hypoxia in patterning of neural and vascular cells recruited to the embryonic heart. Developmental dynamics : an official publication of the American Association of Anatomists 238, 2760-2769. doi:10.1002/dvdy.22103. PMID:19842184

Maltepe, E., Schmidt, J. V., Baunoch, D. et al. (1997). Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein arnt. Nature 386, 403-407. doi:10.1038/386403a0. PMID:9121557

Maltepe, E. and Simon, M. C. (1998). Oxygen, genes, and development: An analysis of the role of hypoxic gene regulation during murine vascular development. Journal of molecular medicine (Berlin, Germany) 76, 391-401. doi:10.1007/s001090050231. PMID:9625296

McCollum, C. W., Conde-Vancells, J., Hans, C. 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. doi:10.1016/j.reprotox.2016.11.005. PMID:27838387

Nimmagadda, S., Geetha Loganathan, P., Huang, R. et al. (2005). Bmp4 and noggin control embryonic blood vessel formation by antagonistic regulation of vegfr-2 (quek1) expression. Developmental biology 280, 100-110. doi:10.1016/j.ydbio.2005.01.005. PMID:15766751

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Vargesson, N. (2015). Thalidomide-induced teratogenesis: History and mechanisms. Birth defects research. Part C, Embryo today : reviews 105, 140-156. doi:10.1002/bdrc.21096. PMID:26043938

Vissapragada, R., Contreras, M. A., da Silva, C. G. et al. (2014). Bidirectional crosstalk between periventricular endothelial cells and neural progenitor cells promotes the formation of a neurovascular unit. Brain research 1565, 44425-44425. doi:10.1016/j.brainres.2014.03.018. PMID:24675025

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Yano, S., Matsumori, Y., Ikuta, K. et al. (2006). Current status and perspective of angiogenesis and antivascular therapeutic strategy: Non-small cell lung cancer. Int J Clin Oncol 11, 73-81. doi:10.1007/s10147-006-0568-3. PMID:16622742

Yeh, J. R., Mohan, R. and Crews, C. M. (2000). The antiangiogenic agent tnp-470 requires p53 and p21cip/waf for endothelial cell growth arrest. Proceedings of the National Academy of Sciences of the United States of America 97, 12782-12787. doi:10.1073/pnas.97.23.12782. PMID:11070090

Yozzo, K. L., Isales, G. M., Raftery, T. D. et al. (2013). High-content screening assay for identification of chemicals impacting cardiovascular function in zebrafish embryos. Environmental science & technology 47, 11302-11310. doi:10.1021/es403360y. PMID:24015875

Zurlinden, T. J., Saili, K. S., Baker, N. C. et al. (2020). A cross-platform approach to characterize and screen potential neurovascular unit toxicants. Reproductive toxicology (Elmsford, N.Y.) 96, 300-315. doi:10.1016/j.reprotox.2020.06.010. PMID:32590145