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Impairment, Endothelial network leads to Altered, Cardiovascular development/function
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Aryl hydrocarbon receptor activation leading to early life stage mortality, via reduced VEGF||adjacent||Moderate||Low||Amani Farhat (send email)||Open for citation & comment||TFHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
The formation of new blood vessels during development occurs via de novo assembly of blood vessels from angioblast precursors (vasculogenesis) and formation of new capillary sprouts from preexisting vessels (angiogenesis) (Ivnitski-Steele and Walker 2005). The epicardium is a single cell layer that spreads over the surface of the heart during embryo development and is the source of angioblasts, which penetrate into the myocardium, providing the endothelial and mural cell progenitor populations that eventually form the entire coronary vasculature (Ivnitski-Steele and Walker 2005; Viragh et al. 1993; Vrancken Peeters et al. 1999). The development of the vasculature into highly branched conduits needs to occur in numerous sites and in precise patterns to supply oxygen and nutrients to the rapidly expanding tissue of the embryo; aberrant regulation and coordination of angiogenic signals during development result in impaired organ development (Chung and Ferrara 2011).
Evidence Supporting this KER
The importance of endothelial cell migration, proliferation and integrity in neovascularization and organogenesis is well documented (Chung and Ferrara 2011; Ivnitski-Steele and Walker 2005).
Uncertainties and Inconsistencies
No uncertainties or inconsistencies to report.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The importance of endothelial integrity for normal cardiac function has been demonstrated in zebrafish (Plavicki et al. 2013) and chicken (Carro et al. 2013; Ivnitski et al. 2001) embryos as well as mammals (Kopf et al 2008; Paulus 1994).
1. Carro, T., Taneyhill, L. A., and Ottinger, M. A. (2013). The effects of an environmentally relevant 58 congener polychlorinated biphenyl (PCB) mixture on cardiac development in the chick embryo. Environ. Toxicol. Chem.
2. Chung, A. S., and Ferrara, N. (2011). Developmental and pathological angiogenesis. Annu. Rev. Cell Dev. Biol. 27, 563-584.
3. Ivnitski, I., Elmaoued, R., and Walker, M. K. (2001). 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibition of coronary development is preceded by a decrease in myocyte proliferation and an increase in cardiac apoptosis. Teratology 64(4), 201-212.
4. Ivnitski-Steele, I., and Walker, M. K. (2005). Inhibition of neovascularization by environmental agents. Cardiovasc. Toxicol. 5(2), 215-226.
5. Plavicki, J., Hofsteen, P., Peterson, R. E., and Heideman, W. (2013). Dioxin inhibits zebrafish epicardium and proepicardium development. Toxicol. Sci. 131(2), 558-567.
6. Viragh, S., Gittenberger-de Groot, A. C., Poelmann, R. E., and Kalman, F. (1993). Early development of quail heart epicardium and associated vascular and glandular structures. Anat. Embryol. (Berl) 188(4), 381-393.
7. Vrancken Peeters, M. P., Gittenberger-de Groot, A. C., Mentink, M. M., and Poelmann, R. E. (1999). Smooth muscle cells and fibroblasts of the coronary arteries derive from epithelial-mesenchymal transformation of the epicardium. Anat. Embryol. (Berl) 199(4), 367-378.
8. Di, M. F., Castaldo, C., Nurzynska, D., Romano, V., Miraglia, R., and Montagnani, S. (2010). Epicardial cells are missing from the surface of hearts with ischemic cardiomyopathy: a useful clue about the self-renewal potential of the adult human heart? Int. J Cardiol. 145(2), e44-e46.
9. Kopf, P. G., Huwe, J. K., and Walker, M. K. (2008). Hypertension, cardiac hypertrophy, and impaired vascular relaxation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin are associated with increased superoxide. Cardiovasc. Toxicol. 8(4), 181-193.
10. Paulus, W. J. (1994). Endothelial control of vascular and myocardial function in heart failure. Cardiovasc. Drugs Ther. 8(3), 437-446.