Altered ratios of pro‐ and anti‐angiogenic VEGF‐A variants and pericyte expression of DLL4 disrupt vascular maturation in infantile haemangioma

摘要

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‐A165b 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‐A165b inhibited cell proliferation and the angiogenic potential of IH endothelial cells in vitro and in vivo. The inhibition of angiogenesis by VEGF‐A165b was associated with the extent of style="fixed-case">VEGF receptor 2 ( style="fixed-case">VEGFR2) activation and degradation and Delta‐like ligand 4 ( style="fixed-case">DLL4) expression. These results indicate that style="fixed-case">VEGF‐A variants can be regulated by cell differentiation and are involved in style="fixed-case">IH progression. We also demonstrated that style="fixed-case">DLL4 expression was not exclusive to the endothelium in style="fixed-case">IH but was also present in pericytes, where the expression of style="fixed-case">VEGFR2 is absent, suggesting that pericyte‐derived style="fixed-case">DLL4 may prevent sprouting during involution, independently of style="fixed-case">VEGFR2. Angiogenesis in style="fixed-case">IH therefore appears to be controlled by style="fixed-case">DLL4 within the endothelium in a style="fixed-case">VEGF‐A isoform‐dependent manner, and in perivascular cells in a style="fixed-case">VEGF‐independent manner. The contribution of style="fixed-case">VEGF‐A isoforms to disease progression also indicates that style="fixed-case">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.