Event:298

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Event Title

Vascular, insufficiency
Short name: Vascular, insufficiency

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
VEGF Signaling and Vascular Disruption Leading to Adverse Developmental Outcomes KE Strong

Taxonomic Applicability

Name Scientific Name Evidence Links

Level of Biological Organization

Biological Organization

How this Key Event works

Blood vessels are key regulators of organogenesis by providing oxygen, nutrients and molecular signals [Maltepe et al. 1997; Chung and Ferrara, 2011; Eshkar-Oren et al. 2015]. Furthermore, vascular disruption has been implicated in the etiology of human birth defects associated with medications taken by women of child-bearing potential (WOCBP) [van Gelder et al. 2009] and a mechanism of teratogenesis in animal studies [Therapontos et al. 2009; Vargesson et al. 2015]. An in vitro signature for potential vascular disrupting chemicals (pVDCs) was thus mined for developmental toxicity based on ToxCast Phase-I dataset [Kleinstreuer et al. 2011] and this signature was subsequently expanded into a comprehensive Adverse Outcome Pathway (AOP) framework for vasculogenesis and angiogenesis [Knudsen and Kleinstreuer, 2011]. This has since been applied to the ToxCast Phase-II inventory to rank order 1060 chemicals based on the functionalized pVDC signature [McCollum et al. 2016; Tal et al. 2016; Knudsen et al. 2016]. As such, a chemical’s potential to disrupt vascular patterning, remodeling, or utero-placental circulation could be a class predictor of developmental toxicity solely based on the ToxCast in vitro data in combination with our understanding the embryology behind vascular development.

How it is Measured or Detected

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

Evidence Supporting Taxonomic Applicability

References

Chung AS, Ferrara N. Developmental and pathological angiogenesis. Annual review of cell and developmental biology. 2011;27:563-84. PubMed PMID: 21756109.

Eshkar-Oren I, Krief S, Ferrara N, Elliott AM, Zelzer E. Vascular patterning regulates interdigital cell death by a ROS-mediated mechanism. Development (Cambridge, England). 2015 Feb 15;142(4):672-80. PubMed PMID: 25617432.

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.

Maltepe E, Schmidt JV, Baunoch D, Bradfield CA, Simon MC. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature. 1997 Mar 27;386(6623):403-7. PubMed PMID: 9121557.

McCollum CW, Vancells JC, Hans C, Vazquez-Chantada M, Kleinstreuer N, Tal T, Knudsen T, Shah SS, Merchant FA, Finnell RH, Gustafsson J-A, Cabrera R and Bondesson M (2016) Identification of vascular disruptor compounds by a tiered analysis in zebrafish embryos and mouse embryonic endothelial cells. (submitted).

Tal T, Kilty C, Smith A, LaLone C, Kennedy B, Tennant A, McCollum C, Bondesson M, Knudsen T, Padilla S and Kleinstreuer N (2016) Screening for chemical vascular disruptors in zebrafish to evaluate a predictive model for developmental vascular toxicity. (submitted).

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.

Vargesson N. Thalidomide-induced teratogenesis: history and mechanisms. Birth defects research Part C, Embryo today : reviews. 2015 Jun;105(2):140-56. PubMed PMID: 26043938.