title: Altered ratios of pro- and anti-angiogenic VEGF-A variants and pericyte expression of DLL4 disrupt vascular maturation in infantile haemangioma.
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 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. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
authors.affiliation: Ophthalmology Unit, School of Clinical Sciences, University of Bristol, UK.|Cancer Biology Unit, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, UK.
authors.forename: Xi
authors.initials: X
authors.lastname: Ye
authors.affiliation: Moorfields Eye Hospital, London, UK.
authors.forename: Yassir
authors.initials: Y
authors.lastname: Abou-Rayyah
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, MA, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Bischoff
authors.affiliation: Cancer Biology Unit, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Ritchie
authors.affiliation: Histopathology, Great Ormond Street Hospital, London, UK.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.affiliation: University Hospital of Wales, Cardiff, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Watts
authors.affiliation: Ophthalmology Unit, School of Clinical Sciences, University of Bristol, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Churchill
authors.affiliation: Cancer Biology Unit, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, UK.
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D002675:Child, Preschool; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006391:Hemangioma / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: angiogenesis; endothelial cell; haemangioma; vascular endothelial growth factor