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

Abstract

BackgroundInfantile 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.ResultsIn 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.ConclusionsWe 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.

Wnt3a Expression is Associated with MMP-9 Expression in Primary Tumor and Metastatic Site in Recurrent or Stage IV Colorectal Cancer

“…Agonists and antagonists of β-ARs are known to act antithetically via the same intracellular pathways [92]. Given that the expression of all three β-ARs has been demonstrated in IH tumors [93][94][95][96], does β-adrenergic signaling play a role in the pathogenesis of IH? This hypothesis was immediately and, to some degree, indirectly testable by Mayer et al [97], who found that intrauterine exposure to β 2 -sympathomimetic hexoprenaline can increase the occurrence of IH in preterm infants, suggesting a role for β-AR stimulation in the initiation of IH.…”

Infantile hemangioma and oral propranolol therapy

“…Beta agonist uyarı, VEGF ve ekstraselüler signal regulated kinase (ERK) inhibitörlerince baskılanabilmektedir. Bunlara dayanılarak propranololun temel etki mekanizması-nın mitoz bölünmenin hücre içi tetiği olan ERK fosforilizasyonunu engellemek olduğu düşünülmekte-dir (14). Sonuç olarak; İnfantil hemanjiom oldukça sık görülen çocukluk yaş grubunun selim vasküler tümö-rüdür.…”

Mechanisms of propranolol action in infantile hemangioma

“…It has been shown that hemECs and other EC types express both b1-and b2-ADRs at very similar levels, but not b3. 52,53 We have shown that normal ECs express all 3 b-ADRs, with b1-ADR expression being significantly higher when compared to the other subtypes. 50 Despite the various b-ADRs expressed, it is believed that the main mechanism of action of propranolol in hemECs may involve b1 and/or 2-ADR pathway.…”