Ye, X;
Abou-Rayyah, Y;
Bischoff, J;
Ritchie, A;
Sebire, NJ;
Watts, P;
Churchill, AJ;
(2016)
Altered ratios of pro- and anti-angiogenic VEGF-A variants and pericyte expression of DLL4 disrupt the vascular maturation in infantile haemangioma.
Journal of Pathology
, 239
(2)
pp. 139-151.
10.1002/path.4715.
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Abstract
Infantile haemangioma (IH), the most common neoplasm in infants, is a slowly resolving vascular tumour. Vascular endothelial growth factor A (VEGF-A), which consists of both the pro- and anti-angiogenic variants, contributes to the pathogenesis of IH. However, the roles of different VEGF-A variants in IH progression and its spontaneous involution is unknown. Using patient derived cells and surgical specimens, we showed that the relative level of VEGF-A165 b was increased in the involuting phase of IH and the relative change in VEGF-A isoforms may be dependent on endothelial differentiation of IH stem cells. VEGFR signalling regulated IH cell functions and VEGF-A165 b inhibited cell proliferation and the angiogenic potential of IH endothelial cells in vitro and in vivo. The inhibition of angiogenesis by VEGF-A165 b was associated with the extent of VEGF receptor 2 (VEGFR2) activation and degradation and Delta Like Ligand 4 (DLL4) expression. These results indicate that VEGF-A variants can be regulated by cell differentiation and are involved in IH progression. We also demonstrated that DLL4 expression was not exclusive to the endothelium in IH but was also present in pericytes, where the expression of VEGFR2 is absent, suggesting that pericyte-derived DLL4 may prevent sprouting during involution independently of VEGFR2. Angiogenesis in IH may therefore appears to be controlled by DLL4 within the endothelium in a VEGF-A isoform dependent manner, and in perivascular cells in a VEGF independent manner. The contribution of VEGF-A isoforms to disease progression also indicates that IH may be associated with altered splicing.
| Type: | Article |
|---|---|
| Title: | Altered ratios of pro- and anti-angiogenic VEGF-A variants and pericyte expression of DLL4 disrupt the vascular maturation in infantile haemangioma |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/path.4715 |
| Publisher version: | http://dx.doi.org/10.1002/path.4715 |
| Language: | English |
| Additional information: | © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in anymedium, provided the original work is properly cited. |
| Keywords: | Angiogenesis, Haemangioma, endothelial cell, vascular endothelial growth factor |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1477457 |
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