From the Departments of Pediatric Surgery and Central Laboratory, Second Hospital of Hebei Medical University.
Plast Reconstr Surg. 2018 Sep;142(3):310e-321e. doi: 10.1097/PRS.0000000000004684.
Propranolol is the first-line drug for treatment of infantile hemangioma. However, its mechanism of action remains unclear. Nuclear factor-κB is highly expressed in tumors, directly or indirectly promoting angiogenesis. Thrombospondin-1 is the most important antiangiogenesis protein in vivo. These proteins mediate signaling pathways, probably playing an important role in hemangioma treatment. This study explored the synergistic regulation of thrombospondin-1 and nuclear factor-κB signaling pathways in the treatment of hemangioma with propranolol.
The hemangioma-derived endothelial cells were sorted out from the specimens of proliferative hemangioma by flow cytometry. Furthermore, a BALB/c nude mouse hemangioma model was established. Viability and proliferation of hemangioma-derived endothelial cells and the role of thrombospondin-1 and nuclear factor-κB signaling pathways were observed after propranolol administration in vitro and in vivo.
The expression of thrombospondin-1 and its receptor CD36 in hemangioma-derived endothelial cells gradually increased with the increase in propranolol concentration, whereas the expression of nuclear factor-κBp65, phosphorylated inhibitor of κB alpha (p-IκBα), and phosphorylated inhibitor of nuclear factor-κB kinase beta (p-IκKβ) weakened gradually (p < 0.05). In vivo, the tumors shrank gradually after propranolol treatment, with an increase in thrombospondin-1 and CD36 and a decrease in nuclear factor-κBp65, p-IκBα, and p-IκKβ (p < 0.05). Glucocorticoid improved the antiangiogenesis mediated by thrombospondin-1/CD36 and inhibited the angiogenesis mediated by nuclear factor-κB/IκB (p < 0.05). Negative regulation occurred between the two signaling pathways.
The treatment of infantile hemangioma with propranolol is promising to promote thrombospondin-1-mediated antiangiogenesis and to block nuclear factor-κB-mediated angiogenesis.
普萘洛尔是治疗婴幼儿血管瘤的一线药物。然而，其作用机制尚不清楚。核因子-κB 在肿瘤中高度表达，直接或间接促进血管生成。血小板反应蛋白-1 是体内最重要的抗血管生成蛋白。这些蛋白介导信号通路，可能在血管瘤的治疗中发挥重要作用。本研究探讨了普萘洛尔治疗血管瘤时血小板反应蛋白-1 和核因子-κB 信号通路的协同调节作用。
通过流式细胞术从增殖期血管瘤标本中分离出血管瘤衍生的内皮细胞。此外，建立了 BALB/c 裸鼠血管瘤模型。观察普萘洛尔在体外和体内对血管瘤衍生内皮细胞的活性和增殖的作用，以及血小板反应蛋白-1 和核因子-κB 信号通路的作用。
随着普萘洛尔浓度的增加，血管瘤衍生内皮细胞中血小板反应蛋白-1 及其受体 CD36 的表达逐渐增加，而核因子-κBp65、磷酸化抑制κB 激酶β（p-IκKβ）的表达逐渐减弱（p < 0.05）。在体内，普萘洛尔治疗后肿瘤逐渐缩小，血小板反应蛋白-1 和 CD36 增加，核因子-κBp65、磷酸化抑制κB 激酶β（p-IκKβ）减少（p < 0.05）。糖皮质激素改善了血小板反应蛋白-1/CD36 介导的抗血管生成作用，并抑制了核因子-κB/IκB 介导的血管生成作用（p < 0.05）。两种信号通路之间存在负向调节。
普萘洛尔治疗婴幼儿血管瘤有望促进血小板反应蛋白-1 介导的抗血管生成，并阻断核因子-κB 介导的血管生成。
