Relationship: 1036
Title
Upstream event
Insufficiency, VascularDownstream event
Increased, Developmental Defects
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 | High | Moderate |
Taxonomic Applicability
Sex Applicability
Life Stage Applicability
Key Event Relationship Description
Evidence Supporting this KER
Empirical Evidence
Vascular endothelial growth factor-A (VEGF-A), in particular the VEGF165 splice variant, plays a key role in the regulation of angiogenesis during early embryogenesis. This is evidenced by immature blood vessel formation and embryonic lethality in mutant mouse embryos heterozygous for the Vegfa-null allele [Ferrara et al. 1996; Carmellet et al. 1996]. Targeted disruption of VEGFR1 or VEGFR2 is early embryonic lethal; however, the vascular phenotypes differ in either case. VEGFR1-mutant (Flt1-null) embryos display excessive endothelial cell growth leading to disorganization of the vascular network [Fong et al. 1995] whereas VEGFR2-mutant (Flk1-null) embryos die from a lack blood vessel network formation [Shalaby et al. 1995].
Quantitative Understanding of the Linkage
Domain of Applicability
References
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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.
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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.