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Role of Thrombospondin-1 and Nuclear Factor-κB Signaling Pathways in Antiangiogenesis of Infantile Hemangioma

Xu, Weili, M.D., Ph.D.; Li, Suolin, M.D.; Yu, Fengxue, M.D., Ph.D.; Zhang, Yongting, B.S.; Yang, Xiaofeng, M.M.; An, Wenting, B.S.; Wang, Wenbo, M.M.; Sun, Chi, M.M.

Plastic and Reconstructive Surgery: September 2018 - Volume 142 - Issue 3 - p 310e-321e
doi: 10.1097/PRS.0000000000004684

Background: 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.

Methods: 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.

Results: 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.

Conclusion: The treatment of infantile hemangioma with propranolol is promising to promote thrombospondin-1–mediated antiangiogenesis and to block nuclear factor-κB–mediated angiogenesis.

Shijiazhuang, Hebei, People’s Republic of China

From the Departments of Pediatric Surgery and Central Laboratory, Second Hospital of Hebei Medical University.

Received for publication May 16, 2017; accepted February 27, 2018.

Presented in part at the 12th Annual Conference of the Chinese Society of Pediatric Surgery, Xi’an City, Shanxi Province, China, September 8-10, 2016.

Disclosure:None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this article.

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Weili Xu, M.D., Ph.D., Department of Pediatric Surgery, Second Hospital of Hebei Medical University, Shijiazhuang 050000, People’s Republic of China,

Copyright © 2018 by the American Society of Plastic Surgeons