| First Author | Soggia A | Year | 2014 |
| Journal | Diabetologia | Volume | 57 |
| Issue | 11 | Pages | 2348-56 |
| PubMed ID | 25186293 | Mgi Jnum | J:218695 |
| Mgi Id | MGI:5618205 | Doi | 10.1007/s00125-014-3365-y |
| Citation | Soggia A, et al. (2014) von Hippel-Lindau gene disruption in mouse pancreatic progenitors and its consequences on endocrine differentiation in vivo: importance of HIF1-alpha and VEGF-A upregulation. Diabetologia 57(11):2348-56 |
| abstractText | 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-alpha (HIF1-alpha) pathway. We aimed to analyse the effects of HIF1-alpha 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-alpha degradation, by crossing Vhl-floxed mice with Sox9-Cre mice. RESULTS: HIF1-alpha 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-alpha 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-alpha negatively controls beta cell differentiation in vivo by regulating NGN3 expression, and that this effect is mediated by signals from blood vessels. |
