Biochemical and Biophysical Research Communications, Vol.378, No.4, 766-771, 2009
Pharmacologically induced angiogenesis in transgenic zebrafish
The rapid vascularisation of biomaterials and engineered tissue after implantation is a current unmet need. To this end, we explored the pharmacological option of inducing neovascularisation using compounds that inhibit hypoxia-induced factor-1 alpha a prolyl hydroxylase. This stabilises hypoxia inducible factor-1 alpha and therefore de-repress the transcription of various angiogenic genes. In the quest for a small vertebrate model allowing for in vivo screening we exposed (TG(Fli1:EGFP)) transgenic zebrafish embryos exhibiting fluorescent blood vessels to hydralazine hydrochloride and 2,4-pyridine dicarboxylic acid from 6 hpf to 72 hpf by immersion. Live observation of embryos revealed that the substances induced formation of ectopic blood vessels in the subintestinal vessel basket. We confirmed the HIF-stabilising effects biochemically in human fibroblasts and with an in vitro angiogenesis fibroblast/HUVEC co-culture model. Cross-inhibition of collagen prolyl hydroxylase was confirmed by reduced collagen secretion by fibroblasts and reduced collagen content of zebrafish embryos. (C) 2008 Elsevier Inc. All rights reserved.
Keywords:Zebrafish;Fli1;Neovascularisation;Prolyl hydroxylase inhibitors;Hypoxia-induced factor-1 alpha;Drug screening;Collagen;Subintestinal vessels