To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:125
Impairment, Endothelial network leads to Insufficiency, Vascular
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Disruption of VEGFR Signaling Leading to Developmental Defects||non-adjacent||Moderate||Low||Tom Knudsen (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
An embryo develops normally only with an adequate supply of oxygen, nutrients, molecular signals, and removal of waste products [Maltepe et al. 1997]. In its early stages this may be satisfied by simple diffusion; however, the rate of diffusion becomes limiting beyond a certain mass. The circulatory system becomes functional early in development and is the first organ system to operate in the vertebrate embryo, reflecting this critical role during organogenesis [Chan et al. 2002; Jin et al. 2005; Walls et al. 2008]. With the onset of cardiac function during early organogenesis the primitive vascular system quickly evolves into a patent circulatory system that transports hematopoietic cells through major blood vessels (e.g., dorsal aorta, cardinal veins, and six aortic arches in the branchial region). Impaired endothelial formation impacts this role in many ways through abnormalities in artery/vein development, vascular remodeling, tissue neovascularization, and microvascular ramifications.
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility: Problems of insufficient blood support due to slow or weak heartbeat, vessel occlusions, or anemia will take a toll on various organ systems depending on the stage of development and regional responses to oxygen-sensing pathways [Maltepe et al. 1998; Liu et al. 2009; Gerri et al. 2017].
Empirical Evidence: Microvascular specializations derived from the perineural vascular plexus (PNVP) surrounding the neural tube and choriovitelline system (CVS) in extraembryonic membranes establish critical transport interfaces with the CNS (e.g., blood-brain barrier and retinal vascularization) [Dorrell et al. 2002; Hogan et al. 2004; Bautch and James, 2009; Eichmann and Thomas, 2013; Vissapragada et al. 2014; Fiorentino et al. 2016; Uwamori et al. 2017; Saili et al. 2017; Huang, 2020] and extraembryonic environment [Abbott and Buckalew, 2000; Chen and Zheng, 2014], respectively. These systems are particularly vulnerable to problems of unstable and leaky vessels in otherwise well-defined endothelial networks.
Uncertainties and Inconsistencies
Uncertainties and Inconsistencies: Blood flow patterns vary in higher vertebrates as vascular anatomy becomes complicated by asymmetrical loss of some vessels and expansion of others, especially in mammals where prenatal circulatory shunts bypass the fetal lungs and liver due to placental function.
Known modulating factors
Quantitative Understanding of the Linkage
A number of anti-angiogenic compounds, including Vatalanib and Thalidomide, have been shown to quantitatively impair vascular patterning [Tran et al. 2007; Therapontos et al. 2009; Jang et al. 2009; Rutland et al. 2009; Tal et al. 2014; Vargesson, 2015; Beedie et al. 2016a; Ellis-Hutchings et al. 2017; Kotini et al. 2020]. In exposed zebrafish embryos, early effects of potential vascular disrupting chemicals (pVDCs) invoke changes to the anatomical development of intersegmental vessels from the dorsal aorta [Tal et al. 2014; McCollum et al. 2017]. Thalidomide, for example, has been shown to primarily disrupt immature vascular networks versus more mature vasculature in the embryo [Therapontos et al. 2009; Beedie et al. 2016a, 2016b, 2017]. Evidence for this KER in human studies is indirect, based solely on correlating malformations with vascular anatomy and/or developmental risks for women of reproductive potential or exposed during pregnancy to anti-angiogenic drugs [Husain et al. 2008; van Gelder et al. 2010; Gold et al. 2011; Ligi et al. 2014; Vargesson and Hootnick, 2017]. Key nodes in the ontogenetic regulation of angiogenesis have been investigated with human cell-based high-throughput assay (HTS) platforms in ToxCast to screen for pVDCs acting on the formation, maturation and/or stabilization of endothelial networks [Houck et al. 2009; Knudsen et al. 2011; Kleinstreuer et al. 2014; Saili et al. 2019; Zurlinden et al. 2020]. These studies show the complexity of crosstalk between genetic signals and responses for vascular patterning versus morphoregulatory systems in general.
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Mammalian Phenotype Browser (MPO) defines ‘abnormal blood vessel morphology’ (MP:0001614) as “any structural anomaly of the network of tubes that carries blood through the body“. They describe abnormalities linked to: (i) specific cell types of the microvasculature (endothelial cells, pericytes, macrophages); (ii) diversification of arterial, venous, and lymphatic channels; and (iii) organ-specific vascular morphologies including malformations, variations, and pathologies. The subordinate term ‘abnormal vascular development‘ (MP:0000259) defines an “aberrant process of vascular formation“ that neatly captures the biology relevant to this KER. There are 1045 genotypes and 1768 annotations associated with this term (last accessed December 24, 2021).
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.