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.

婴儿血管瘤（IH）是最常见的良性血管肿瘤，由血管内皮细胞过度增殖引起。据报道，在包括IH在内的多种肿瘤的治疗中，从莪术中提取的化合物β-榄香烯具有抗肿瘤作用。然而，β-榄香烯在血管瘤中的潜在机制尚未得到研究。在这项研究中，功能分析表明，低浓度的β-榄香烯促进人血管瘤内皮细胞（HemEC）的增殖、迁移和管形成，而高浓度的β-榄香烯则产生抑制作用。此外，我们还发现婴儿血管瘤组织中血管紧张素转换酶 2 (ACE2) 的 mRNA 和蛋白水平表达均下调，而缺氧诱导因子 1 α (HIF-1-α) 表达上调。 mRNA 和蛋白质水平的 HemEC。该结果表明ACE2和HIF-1-α在IH中发挥作用。不同剂量点β-榄香烯处理后ACE2表达下调。有趣的是，HemECs中血管内皮生长因子-A（VEGFA）的表达随着低浓度β-榄香烯的处理而增加，相反，VEGFA的表达随着高浓度的β-榄香烯的处理而减少。此外，如果β-榄香烯的浓度达到40μg/ml或更高，HIF-1-α的表达降低。 综上所述，我们的数据表明，不同浓度的β-榄香烯对血管瘤的增殖、迁移和血管生成的影响不同：低浓度β-榄香烯处理时，ACE2信号通路占主导地位，刺激下游VEGFA的表达，促进血管瘤的增殖、迁移和血管生成。血管瘤的血管生成；高浓度β-榄香烯条件下，HIF-1-α信号通路抑制VEGFA的表达，进一步抑制血管瘤的血管生成。