Clinical and experimental pharmacology & physiology

Hypoxia-inducible factor 1 activation from adipose protein 2-cre mediated knockout of von Hippel-Lindau gene leads to embryonic lethality.

PMID 22150821


von Hippel-Lindau protein, an E3 ubiquitin ligase from the von Hippel-Lindau (Vhl) gene, inhibits the transcriptional activity of hypoxia-inducible factor 1α in cells. To gain insight into the hypoxia-inducible factor 1α signalling pathway in adipose tissue, a study was conducted to generate fat-specific Vhl knockout mice. Cre-recombinase (Cre)/locus of crossover in P1(loxP) technology was used in the knockout study. The mice carrying floxed-Vhl alleles were crossed with adipose protein 2 (aP2)-Cre mice, in which the Cre gene is driven by the aP2 (fatty acid binding protein 4) gene promoter. The homozygous knockout mice exhibited embryonic lethality at E14.5-E18.5. The homozygous embryos suffered from haemorrhages in the brain and liver. Hypoxia-inducible factor 1α protein and its target gene protein, vascular endothelial growth factor, increased in the brain and liver. Endothelial proliferation and capillary leakage were observed in the tissues. Heterozygous knockout mice appeared normal in development, growth and reproductivity. β-galactosidase reporter mice were used in the analysis of tissue-specificity of Cre in aP2-Cre mice. Strong Cre activity was observed in the dorsal hindbrain region and vertebrae of E12.5 embryos. These results suggest that in the aP2-Cre mice, the recombinase activity is expressed in the central nervous system of the embryos. Central and peripheral haemorrhages are responsible for the embryonic lethality in the homozygous knockout mice.