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.
Diabetologia
; 57(11): 2348-56, 2014 Nov.
Article
in En
| MEDLINE
| ID: mdl-25186293
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pancreas
/
Vascular Endothelial Growth Factor A
/
Von Hippel-Lindau Tumor Suppressor Protein
/
Hypoxia-Inducible Factor 1, alpha Subunit
Limits:
Animals
/
Pregnancy
Language:
En
Journal:
Diabetologia
Year:
2014
Type:
Article
Affiliation country:
France