β-elemene affects angiogenesis of infantile hemangioma by regulating angiotensin-converting enzyme 2 and hypoxia-inducible factor-1 alpha

Infantile hemangioma (IH) is the most common benign vascular tumor resulting from the hyper-proliferation of vascular endothelial cells. In treatment of various tumors including IH, β-elemene, a compound extracted from Rhizoma zedoariae, has been reported to have anti-tumor effect. However, the underlying mechanisms of β-elemene in hemangioma have remained uninvestigated. In this presented study, functional analysis showed that low concentrations of β-elemene promoted the proliferation, migration and tube formation of human hemangioma endothelial cells (HemECs), while high concentrations of β-elemene produced inhibitory effects. Further, we also found that angiotensin-converting enzyme 2 (ACE2) expression was down-regulated at both mRNA and protein levels, while hypoxia-inducible factor-1 alpha (HIF-1-α) was up-regulated in infantile hemangiomas tissues and HemECs at both mRNA and protein levels. This result suggested that ACE2 and HIF-1-α play roles in IH. ACE2 expression was down-regulated with the treatment of β-elemene at different dosage point. Interestingly, the expression of Vascular endothelial growth factor-A (VEGFA) increased with treatment of low concentrations of β-elemene in HemECs, in contrary, the expression of VEGFA expression decreased with treatment of high concentrations of β-elemene. Moreover, if the concentration of β-elemene reached 40 μg/ml or higher, the expression of HIF-1-α decreased. Taken together, our data indicated that the different effects of β-elemene on the proliferation, migration and angiogenesis of hemangioma at different concentrations: The ACE2 signaling pathway dominates with treatment of low concentrations of β-elemene, stimulating the expression of downstream VEGFA to promote the angiogenesis of hemangioma; under the condition of high concentrations of β-elemene, the HIF-1-α signaling pathway inhibits the expression of VEGFA and further inhibits the angiogenesis of hemangioma.