API

Relationship: 975

Title

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reduced production, VEGF leads to Impairment, Endothelial network

Upstream event

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reduced production, VEGF

Downstream event

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Impairment, Endothelial network

Key Event Relationship Overview

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AOPs Referencing Relationship

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

Taxonomic Applicability

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Term Scientific Term Evidence Link
chicken Gallus gallus Strong NCBI
fish fish Strong NCBI
mammals mammals Strong NCBI

Sex Applicability

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Sex Evidence
Unspecific Strong

Life Stage Applicability

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Term Evidence
Embryo Strong
Development Strong

How Does This Key Event Relationship Work

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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

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Biological Plausibility

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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

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Include consideration of temporal concordance here

  • Chick explants (cell culture derive from treated embryos) with reduced endothelial tube length (40%±1.7%) and number (36%±3%) relative to controls,  were rescued by exogenous VEGF treatment or hypoxia (i.e. endothelial tube length and number were increased). The increase by hypoxia was prevented by VEGF neutralizing antibody (Ivnitski-Steele and Walker 2003)
  • Hearts from TCDD treated embryos, which exhibited altered cardiovascular growth, showed sig. reduction in VEGF mRNA and protein (Ivnitski-Steele and Walker 2003)
  • Reduced coronary artery number in chick embryos and reduced tube outgrowth were associated with reduced VEGF-A secretion (43±3%) in vitro (Ivnitski-Steele et al. 2005)
  • In the absence of VEGF-A, human primary umbilical vein endothelial cells (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

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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

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The quantitative understanding of this linkage is poor.

Evidence Supporting Taxonomic Applicability

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The role of VEGF in vasculogenesis and angiogenesis (which include endothelial cell formation, migration and assemply) has been demostrated in chicken[4], fish[8,9] and mammals[7].

References

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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.

6. Cecilia Y. Cheung (1997) Vascular Endothelial Growth Factor: Possible Role in Fetal Development and Placental Function. J Soc Gynecol Invest. 4: 169-77

7. Ahluwalia, A., and Tarnawski, A. S. (2012). Critical role of hypoxia sensor--HIF-1alpha in VEGF gene activation. Implications for angiogenesis and tissue injury healing. Curr. Med. Chem. 19(1), 90-97.

8. Zhu, D., Fang Y., Gao,  K., Shen, J., Zhong, T.P., and Li,  F. (2017) Vegfa Impacts Early Myocardium Development in Zebrafish. Int J Mol Sci. 18(2): 444.

9. Vuori, K.A.M., Soitamo, A., Vuorinen, P.J., and Nikinmaa, M. (2004) Baltic salmon (Salmo salar) yolk-sac fry mortality is associated with disturbances in the function of hypoxia-inducible transcription factor (HIF-1α) and consecutive gene expression. Aquatic Toxicology 68: 301–313