Relationship: 976



Impairment, Endothelial network leads to Altered, Cardiovascular development/function

Upstream event


Impairment, Endothelial network

Downstream event


Altered, Cardiovascular development/function

Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Directness Weight of Evidence Quantitative Understanding
Aryl hydrocarbon receptor activation leading to embryolethality via cardiotoxicty directly leads to Moderate Weak

Taxonomic Applicability


Term Scientific Term Evidence Link
chicken Gallus gallus Strong NCBI
zebrafish Danio rerio Strong NCBI
mammals mammals Strong NCBI

Sex Applicability


Sex Evidence
Unspecific Strong

Life Stage Applicability


Term Evidence
Embryo Strong
Development Strong
Adult Moderate

How Does This Key Event Relationship Work


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).

Weight of Evidence


Biological Plausibility


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).

Empirical Support for Linkage


Include consideration of temporal concordance here

  • 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced cardiotoxicity in zebrafish coincides with epicardium formation. Cardiotoxicity begins at 48 hours post fertilization (hpf; start of pre-epicardium formation) and starts to decline at 5 days post fertilization, which is about the time the initial epicardial cell layer is complete. Cardiotoxicity disappears at 2 weeks, after epicardium formation is complete. TCDD prevented the formation of the epicardial cell layer when exposed 4hpf, and blocked epicardial expansion from the ventricle to the atrium following exposure at 96hpf. These effects ultimately result in valve malformation, reduced heart size, impaired development of the bulbus arteriosus, decreased cardiac output, reduced end diastolic volume, decreased peripheral blood flow, edema and death (Plavicki et al. 2013).
  • Significant decreases in cardiomyocyte proliferation and thinning of the ventricular wall were observed in chicken embryos exposed to PCB58 (Carro et al. 2013).
  • TCDD inhibition of coronary development is preceded by a decrease in myocyte proliferation and an increase in cardiac apoptosis (Ivnitski et al. 2001)
  • Sectioned and stained heart samples from patients with ischemic heart disease lack epicardial cells (Di et al. 2010)
  • Juvenile mice with induced cardiovascular disease show altered heart morphology and function, including epithelial dysfunction (Kopf et al. 2008).

Uncertainties or Inconsistencies


No uncertainties or inconsistencies to report.

Quantitative Understanding of the Linkage


This relationship has not been quantitatively described.

Evidence Supporting Taxonomic 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.