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Diabetologia. 2014 Nov;57(11):2348-56. doi: 10.1007/s00125-014-3365-y. Epub 2014 Sep 4.

von Hippel-Lindau gene disruption in mouse pancreatic progenitors and its consequences on endocrine differentiation in vivo: importance of HIF1-α and VEGF-A upregulation.

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1
U1016 Inserm/Institut Cochin, Groupe Hospitalier Cochin Port-Royal, Bâtiment Cassini, 123 Boulevard du Port-Royal, 75014, Paris, France.

Abstract

AIM/HYPOTHESIS:

Different studies have linked hypoxia to embryonic development. Specifically, when embryonic pancreases are cultured ex vivo under hypoxic conditions (3% O2), beta cell development is impaired. Different cellular signalling pathways are involved in adaptation to hypoxia, including the ubiquitous hypoxia-inducible-factor 1-α (HIF1-α) pathway. We aimed to analyse the effects of HIF1-α stabilisation on fetal pancreas development in vivo.

METHODS:

We deleted the Vhl gene, which encodes von Hippel-Lindau protein (pVHL), a factor necessary for HIF1-α degradation, by crossing Vhl-floxed mice with Sox9-Cre mice.

RESULTS:

HIF1-α was stabilised in pancreatic progenitor cells in which the HIF pathway was induced. The number of neurogenin-3 (NGN3)-expressing cells was reduced and consequently endocrine development was altered in Vhl knockout pancreases. HIF1-α stabilisation induced Vegfa upregulation, leading to increased vascularisation. To investigate the impact of increased vascularisation on NGN3 expression, we used a bioassay in which Vhl mutant pancreases were cultured with or without vascular endothelial growth factor (VEGF) receptor 2 (VEGF-R2) inhibitors (e.g. Ki8751). Ex vivo analysis showed that Vhl knockout pancreases developed fewer NGN3-positive cells compared with controls. Interestingly, this effect was blocked when vascularisation was inhibited in the presence of VEGF-R2 inhibitors.

CONCLUSIONS/INTERPRETATION:

Our data demonstrate that HIF1-α negatively controls beta cell differentiation in vivo by regulating NGN3 expression, and that this effect is mediated by signals from blood vessels.

PMID:
25186293
DOI:
10.1007/s00125-014-3365-y
[Indexed for MEDLINE]

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