Upstream eventreduced production, VEGF
Impairment, Endothelial network
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Aryl hydrocarbon receptor activation leading to embryolethality via cardiotoxicity||adjacent||High||Low|
Life Stage Applicability
Key Event Relationship Description
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).
Evidence Supporting this KER
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).
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 and 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
The quantitative understanding of this linkage is poor.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The role of VEGF in vasculogenesis and angiogenesis (which include endothelial cell formation, migration and assemply) has been demostrated in chicken, fish[8,9] and mammals.
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