The role of β-adrenergic receptor signaling in the proliferation of hemangioma-derived endothelial cells

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.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.Infantile hemangioma (IH) is the most common form of vascular tumor, affecting 5% to 10% of all infants and up to 30% of premature infants [1,2]. IHs occur more frequently in females than in males (at a ratio of 3:1) [3] and generally appear within the first weeks postpartum, proliferate rapidly during the first years of life, and spontaneously involute over a subsequent period of several years. The proliferating and involuting phases of IHs represent a gradual shift in the balance of the mitotic and apoptotic activities of the local endothelial cell population [4]. It has been demonstrated that vascular endothelial growth factor (VEGF) is inv