Manipulation of the HIF-Vegf pathway rescues methyl tert-butyl ether (MTBE)-induced vascular lesions
- Authors
- Bonventre, J.A., Kung, T.S., White, L.A., and Cooper, K.R.
- ID
- ZDB-PUB-131115-19
- Date
- 2013
- Source
- Toxicology and applied pharmacology 273(3): 623-34 (Journal)
- Registered Authors
- Keywords
- vascular toxicity, methyl tert-butyl ether, vascular endothelial growth factor, hypoxia inducible factor, N-oxalylglycine, von Hippel-Lindau protein
- Datasets
- GEO:GSE46371
- MeSH Terms
-
- Animals
- Cell Line, Tumor
- Down-Regulation
- Hypoxia-Inducible Factor 1/genetics
- Hypoxia-Inducible Factor 1/metabolism*
- Methyl Ethers/toxicity*
- Neovascularization, Physiologic/drug effects
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Signal Transduction
- Transcriptome
- Vascular Diseases/chemically induced
- Vascular Diseases/drug therapy*
- Vascular Diseases/genetics
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism*
- Von Hippel-Lindau Tumor Suppressor Protein/genetics
- Von Hippel-Lindau Tumor Suppressor Protein/metabolism
- Zebrafish/embryology
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 24128854 Full text @ Tox. App. Pharmacol.
- CTD
- 24128854
Methyl tert-butyl ether (MTBE) has been shown to be specifically anti-angiogenic in piscine and mammalian model systems at concentrations that appear non-toxic in other organ systems. The mechanism by which MTBE targets developing vascular structures is unknown. A global transcriptome analysis of zebrafish embryos developmentally exposed to 0.00625–5 mM MTBE suggested that hypoxia inducible factor (HIF)-regulated pathways were affected. HIF-driven angiogenesis via vascular endothelial growth factor (vegf) is essential to the developing vasculature of an embryo. Three rescue studies were designed to rescue MTBE-induced vascular lesions: pooled blood in the common cardinal vein (CCV), cranial hemorrhages (CH), and abnormal intersegmental vessels (ISV), and test the hypothesis that MTBE toxicity was HIF–Vegf dependent. First, zebrafish vegf-a over-expression via plasmid injection, resulted in significantly fewer CH and ISV lesions, 46 and 35% respectively, in embryos exposed to 10 mM MTBE. Then HIF degradation was inhibited in two ways. Chemical rescue by N-oxaloylglycine significantly reduced CCV and CH lesions by 30 and 32% in 10 mM exposed embryos, and ISV lesions were reduced 24% in 5 mM exposed zebrafish. Finally, a morpholino designed to knock-down ubiquitin associated von Hippel–Lindau protein, significantly reduced CCV lesions by 35% in 10 mM exposed embryos. In addition, expression of some angiogenesis related genes altered by MTBE exposure were rescued. These studies demonstrated that MTBE vascular toxicity is mediated by a down regulation of HIF–Vegf driven angiogenesis. The selective toxicity of MTBE toward developing vasculature makes it a potentially useful chemical in the designing of new drugs or in elucidating roles for specific angiogenic proteins in future studies of vascular development.