Upstream eventImpairment, Endothelial network
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Disruption of VEGFR Signaling Leading to Developmental Defects||non-adjacent||Moderate||Low|
Life Stage Applicability
Key Event Relationship Description
In utero vascular disruptions are thought to be associated with a variety of developmental defects [Husain et al. 2008]. Vascular disruption was identified as one of 6 teratogenic mechanisms linked with medications [van Gelder et al. 2010].
Evidence Supporting this KER
In humans, the most common apparent cause of limb deficiencies was found to be vascular disruption defects [Gold et al. 2011]. Many genetic and environmental factors alter molecular pathways regulating angiogenesis [Knudsen and Kleinstreuer, 2011].
Susceptibility to Thalidomide linked to the disruption of immature angiogenic network at time of exposure [Therapontos et al. 2009]. Predicted vascular disrupting chemicals in ToxCast correlate with developmental toxicity [Kleinstreuer et al. 2011].
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Quantitative understanding of the linkage is not well established for mammalian systems; however, a clear concentration- and time-dependent relationship has been demonstrated in transgenic zebrafish embryos exposed to a VEGFR2 inhibitor (Vatalanib). Quantitative effects on angiogenesis forshadowed, both in concentration and time, the morphological effects on larva and this extended even to survival curves at 30 days post-hatching. [Tal et al. 2014].
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.