Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action

Abstract

Infantile haemangiomas (IH) are the most common benign tumours of infancy. Although most IH are innocuous and 85-90% regress spontaneously, some may become life- or function-threatening and require immediate treatment. Previous standard therapeutic options include physical measures (laser surgery, cryosurgery) and systemic corticosteroids, in severe cases also vincristine, alpha-interferon or cyclophosphamide, all bearing the risk of serious side-effects. Oral propranolol is a very recent therapeutic option for complicated IH with impressive efficacy and generally good tolerance. The effects of propranolol on IH were discovered by chance, and very little is known about its mechanisms of action in IH. Here we present a summary of current knowledge of how propranolol interferes with endothelial cells, vascular tone, angiogenesis and apoptosis. Early, intermediate and long-term effects of propranolol on IH can be attributed to three different pharmacological targets. Early effects (brightening of the haemangioma surface within 1-3 days after start of therapy) are attributable to vasoconstriction due to decreased release of nitric oxide. Intermediate effects are due to the blocking of proangiogenic signals (vascular endothelial growth factor, basic fibroblast growth factor, matrix metalloproteinase 2/9) and result in growth arrest. Long-term effects of propranolol are characterized by induction of apoptosis in proliferating endothelial cells, and result in tumour regression.

The Use of Sodium Tetradecyl Sulphate for the Treatment of Venous Malformations of the Head and Neck

“…In contrast, Hemangiomas are active proliferating tumors which demonstrate a characteristic pattern of rapid postnatal growth followed by slow involution [2,3]. Although the serendipitous discovery of the therapeutic efficacy of propranolol in the management of infantile hemangiomas has revolutionized the care and outcomes of these lesions [5,6], there is no standard treatment protocol for the management of VM. Treatment options of low flow VM include simple observation, minimally invasive interventions such as sclerotherapy or embolization [7,8], laser ablation [9], cryotherapy [10], or more aggressive surgical resection.…”

β-Adrenergic receptor expression in vascular tumors

“…In addition, activation of bARs results in the synthesis of proangiogenic factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which activate proangiogenic cascades [extracellular signal-related kinases/mitogen-activated protein kinases (MAPK) cascade] promoting angiogenesis. [19][20][21] Also, activation of b-ARs inhibits apoptosis mediated by Src tyrosine kinase, MAPK, and caspase cascades. 20 PKA can phosphorylate b1 and b2-ARs, resulting in uncoupling and internalization.…”

“…[19][20][21] Also, activation of b-ARs inhibits apoptosis mediated by Src tyrosine kinase, MAPK, and caspase cascades. 20 PKA can phosphorylate b1 and b2-ARs, resulting in uncoupling and internalization. 22 Dephosphorylation ensues, followed by recycling of the receptor to the cell membrane.…”

“…23,24 Propranolol, a nonselective b-AR antagonist, has been hypothesized to treat infantile hemangiomas via vasoconstriction, inhibition of angiogenesis, and induction of apoptosis. 20 Propranolol-induced vasoconstriction is thought to be mediated through inhibition of eNOS and NO release, resulting in the change in color and palpable softening seen in infantile hemangiomas with the onset of propranolol treatment. 20 In a prior report, we identified the immunohistochemical expression of b2-AR (B2-AR) and its phosphorylated form (B2-ARP) in a case of infantile hemangioma responding to propranolol treatment.…”

“…20 Propranolol-induced vasoconstriction is thought to be mediated through inhibition of eNOS and NO release, resulting in the change in color and palpable softening seen in infantile hemangiomas with the onset of propranolol treatment. 20 In a prior report, we identified the immunohistochemical expression of b2-AR (B2-AR) and its phosphorylated form (B2-ARP) in a case of infantile hemangioma responding to propranolol treatment. 17 The B2-AR demonstrated cytoplasmic staining within the endothelial cells and arteriole smooth muscle.…”