Department of Plastic Surgery, Case Western Reserve University, Cleveland, OH 44106, USA.
Ann Surg. 2012 Jul;256(1):146-56. doi: 10.1097/SLA.0b013e318254ce7a.
To investigate the mechanism of propranolol on regression of infantile hemangiomas.
Propranolol has been found to be effective in treatment of severe hemangiomas of infancy. However, its mechanism of action is as yet unknown.
Cultured proliferating and involuting hemangioma endothelial cells were treated with varying concentrations of propranolol for up to 4 days. Analysis was performed using cell viability, migration, and tubulogenesis assays, as well as quantitative RT-PCR and flow cytometry. Western blots and ELISA assays were used to assess protein expression.
Treatment with propranolol led to a dose dependent cytotoxic effect in hemangioma endothelial cells with decreased cell viability, migration, and tubulogenesis. This cytotoxic effect was VEGF (vascular endothelial growth factor) dependent, as demonstrated by decreased VEGF, VEGF-R1, and VEGF-R2 production. Decreased signaling through the VEGF pathway resulted in downregulation of PI3/Akt and p38/MAPK activity. Decreased VEGF activity was mediated through the hypoxia inducible factor (HIF)-1α pathway but not through NF-κβ signaling.
Collectively, these data suggest that propranolol exerts its suppressive effects on hemangiomas through the HIF-1α-VEGF-A angiogenesis axis, with effects mediated through the PI3/Akt and p38/MAPK pathways. These findings provide a plausible mechanism of action of propranolol on regression of infantile hemangiomas.
研究普萘洛尔治疗婴幼儿血管瘤消退的作用机制。
普萘洛尔治疗婴幼儿严重血管瘤已被证实有效，但作用机制尚未明确。
采用不同浓度的普萘洛尔处理增殖期和消退期血管瘤内皮细胞，培养 4 天。采用细胞活力、迁移和管状形成测定、实时定量 RT-PCR 和流式细胞术分析。Western blot 和 ELISA 检测评估蛋白表达。
普萘洛尔治疗导致血管瘤内皮细胞出现剂量依赖性细胞毒性，细胞活力、迁移和管状形成减少。这种细胞毒性作用依赖于 VEGF（血管内皮生长因子），因为 VEGF、VEGF-R1 和 VEGF-R2 的产生减少。VEGF 通路信号降低导致 PI3/Akt 和 p38/MAPK 活性下调。VEGF 活性降低是通过缺氧诱导因子（HIF）-1α 途径介导的，而不是通过 NF-κβ 信号。
综上所述，这些数据表明，普萘洛尔通过 HIF-1α-VEGF-A 血管生成轴对血管瘤发挥抑制作用，通过 PI3/Akt 和 p38/MAPK 通路介导。这些发现为普萘洛尔治疗婴幼儿血管瘤提供了一种可能的作用机制。
