title: The role of β-adrenergic receptor signaling in the proliferation of hemangioma-derived endothelial cells.
abstract: BACKGROUND
  Infantile hemangioma (IH) is a benign vascular neoplasm that arises from the abnormal proliferation of endothelial cells and enhanced angiogenesis. Recently, propranolol has been found to be effective in the management of IH, suggesting that β-adrenergic receptors (β-ARs) may play an important role in the pathogenesis of IH.
  
  
  RESULTS
  In the present study, we investigated the β-adrenergic signaling that is associated with hemangioma-derived endothelial cell (HemEC) proliferation. The results showed that both β1- and β2-ARs were expressed in HemECs. Stimulation of the β-ARs by isoprenaline induced cell proliferation and elevation of second messenger cAMP levels. The proliferation-promoting action of isoprenaline was abolished by a β1-selective antagonist and was more effectively abolished by a β2-selective antagonist; the mechanism for the action of the antagonists was a G0/G1 phase cell cycle arrest which was associated with decreased cyclin D1, CDK-4, CDK-6 and phospho-Rb expression. Pre-treatment of the cells with VEGFR-2 or ERK inhibitors also prevented the isoprenaline-mediated proliferation of cells. In agreement with the involvement of β-ARs and VEGFR-2 in the HemEC response, β-AR antagonists and the VEGFR-2 inhibitor significantly attenuated isoprenaline-induced ERK phosphorylation. Moreover, treating the cells with isoprenaline markedly increased VEGF-A expression and VEGFR-2 activity in a β2-AR-dependent manner.
  
  
  CONCLUSIONS
  We have demonstrated that the activation of the β-ARs in the ERK pathway may be important mechanisms in promoting HemEC growth. Furthermore, stimulation of the β-AR may transactivate VEGFR-2 signaling and further increase HemEC proliferation.
authors.affiliation: Division of Oncology, Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Research Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, 201102, China.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Division of Oncology, Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: Division of Oncology, Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
authors.forename: Xianmin
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Division of Oncology, Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Division of Oncology, Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Xu