Expression and association of VEGF-Notch pathways in infantile hemangiomas

The vascular endothelial growth factor (VEGF) and Notch signaling pathways have been identified to be involved in the neovascularization, and angiogenesis of various tumor types. However, there is little data regarding their roles and association in infantile hemangiomas (IHs). In the present study, the significance and association of the VEGF-VEGF receptor (R)2, and δ like canonical Notch ligand 4 (Dll4)-Notch1 pathways in different clinical phases of IHs were investigated. Specimens in the proliferating phase (n=15) and involuting phase (n=12) were collected. Quantitative polymerase chain reaction was used to analyze the mRNA levels of VEGF, VEGFR2, Dll4 and Notch1. A further 61 paraffin-embedded IHs (26 in the proliferating group and 35 in the involuting group) specimens were collected to investigate the protein levels of Notch1 and Dll4 using immunohistochemistry, and then analyzed for the association between these factors and microvessel density (MVD). The relative expression levels of VEGF, VEGFR2 and Dll4 mRNA in the proliferating group were significantly higher compared with that in the involuting group. In addition, the relative levels of Notch1 mRNA were similar in the proliferating and involuting phases. Expression levels of VEGFR2 and Dll4 mRNA were positively correlated with Notch1 expression in the proliferating IHs. The relative expression of VEGFR mRNA was positively correlated with Dll4 in the proliferating and involuting groups. Immunohistochemical staining demonstrated that Notch1 and Dll4 protein were upregulated in the proliferating IHs compared with the control group. In the proliferating IHs, Notch1 and Dll4 protein expression levels were positively correlated with MVD, while in the involuting phase, only Dll4 was positively correlated with MVD. The expression levels of related factors in the VEGF and Notch pathways, and the associations among them suggest that they may be involved in the regulation of IH neovascularization and angiogenesis.