Relationship:975

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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
VEGF, reduced production Endothelial network, Impairment

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
Aryl hydrocarbon receptor activation leading to embryolethality via cardiotoxicty Directly Leads to Strong Weak

Taxonomic Applicability

Name Scientific Name Evidence Links

How Does This Key Event Relationship Work

During vasculogenesis, angioblasts, which express vascular endothelial growth factor (VEGF) receptor 2 (fetal liver kinase; Flk-1), are stimulated to proliferate and differentiate into endothelial cells by VEGF-A. These endothelial cells then assemble into patent capillary tubes via stimulation of VEGF receptor 1 (fms-like tyrosine kinase; Flt-1) by VEGF-A. The endothelial cells then are activated by angiogenic stimuli (such as basic fibroblast growth factor and VEGF-A) to migrate and proliferate, producing new capillary sprouts (Ivnitski-Steele and Walker 2005).

Weight of Evidence

Biological Plausibility

The importance of VEGF for endothelial network formation and integrity is clear (Ivnitski-Steele and Walker 2005); loss of a single VEGF-A allele results in defective vascularization and early embryonic lethality (Carmeliet et al. 1996; Ferrara et al. 1996).

Empirical Support for Linkage

Include consideration of temporal concordance here

  • Endothelial tube length (40%±1.7%) and number (36%±3%) significantly reduced in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TDCC) treated chick explants (cell culture derive from treated embryos); exogenous VEGF, or hypoxia increased length and number to control levels ( i.e. rescued effect of TCDD). The increase by hypoxia was prevented by VEGF neutralizing antibody (Ivnitski-Steele and Walker 2003)
  • Hearts from TCDD treated embryos showed sig. reduction in VEGF mRNA and protein (Ivnitski-Steele and Walker 2003)
  • TCDD reduced coronary artery number in chick embryos by 53±8% and reduced tube outgrowth and VEGF-A secretion (43±3%) in vitro (Ivnitski-Steele et al. 2005)
  • TCDD reduces human primary umbilical vein endothelial cells (HUVEC) basal proliferation by approx. 50% compared to control and reduces VEGF-A-stimulated proliferation by an additional 30%. In the absence of VEGF-A, HUVECs from control cultures elongate and form linear attachments, while addition of VEGF-A stimulates formation of complex interconnected networks (Ivnitski-Steele and Walker 2005).


Uncertainties or Inconsistencies

Reduced secretion of VEGF is not the sole mechanism responsible for reduced coronary vasculogenesis as TCDD caused a dose-related reduction in tube outgrowth in vitro but all doses reduced VEGF-A secretion equally (Ivnitski-Steele et al. 2005).

Quantitative Understanding of the Linkage

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Evidence Supporting Taxonomic Applicability

References


1. Carmeliet, P., Ferreira, V., Breier, G., Pollefeyt, S., Kieckens, L., Gertsenstein, M., Fahrig, M., Vandenhoeck, A., Harpal, K., Eberhardt, C., Declercq, C., Pawling, J., Moons, L., Collen, D., Risau, W., and Nagy, A. (1996). Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380(6573), 435-439.

2. Ferrara, N., Carver-Moore, K., Chen, H., Dowd, M., Lu, L., O'Shea, K. S., Powell-Braxton, L., Hillan, K. J., and Moore, M. W. (1996). Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380(6573), 439-442.

3. Ivnitski-Steele, I., and Walker, M. K. (2005). Inhibition of neovascularization by environmental agents. Cardiovasc. Toxicol. 5(2), 215-226.

4. Ivnitski-Steele, I. D., Friggens, M., Chavez, M., and Walker, M. K. (2005). 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibition of coronary vasculogenesis is mediated, in part, by reduced responsiveness to endogenous angiogenic stimuli, including vascular endothelial growth factor A (VEGF-A). Birth Defects Res. A Clin Mol. Teratol. 73(6), 440-446.

5. Ivnitski-Steele, I. D., and Walker, M. K. (2003). Vascular endothelial growth factor rescues 2,3,7,8-tetrachlorodibenzo-p-dioxin inhibition of coronary vasculogenesis. Birth Defects Res. A Clin Mol. Teratol. 67(7), 496-503.