β1-Adrenoceptor mRNA level reveals distinctions between infantile hemangioma and vascular malformations

Abstract

Background: Infantile hemangioma (Ih) is the most frequent vascular tumor of early childhood. Recently, propranolol, a nonselective β 1 -and β 2 -adrenoceptor inhibitor, was introduced into the therapy of severe proliferating Ih with excellent results. however, the underlying mechanism of action of propranolol is still unclear. Methods: We performed immunohistochemistry for cluster of differentiation 31 (cD31), D2-40, glucose transporter-1 (GLUT-1), and Ki67 in order to characterize 21 vascular anomalies (nine Ih, seven venous malformations (VMs), and five lymphatic malformations (LMs)). Furthermore, we analyzed the expression of β 1 -, β 2 -, and β 3 -adrenoceptor mRNA in these specimens as well as in hemangioma-derived stem cells by quantitative real-time PcR (qPcR). results: We show that the expression of β 1 -adrenoceptor mRNA is 10.7-fold higher in Ih independent of the proliferative or regressive phase as well as 2.5-fold higher in hemangioma-derived stem cells as compared with β 2 -adrenoceptor mRNA. In LM, the expression of β 2 -adrenoceptor mRNA was ninefold higher than that of β 1 -adrenoceptor mRNA. VM showed low expression levels of all β-adrenoceptor mRNAs, and β 3 -adrenoceptor mRNA was hardly detectable in any specimens examined. conclusion: These results provide the first evidence of distinctions between Ih and vascular malformations with regard to β-adrenoceptor subtype mRNA levels. r ecently, propranolol, a nonselective β-adrenoceptor inhibitor, was introduced into the therapy of severe proliferating infantile hemangioma (IH) (1). Propranolol treatment in IH results in fast growth inhibition and rapid tumor regression within a few days of therapy. This novel medical treatment has not been developed in a classic way; it was accidentally observed during corticosteroid therapy, the so far standard therapy for proliferating IH (2) when cardiac hypertrophy as a side effect is treated by propranolol. The molecular mechanism of propranolol on IH proliferation is unknown at present. A possible method of action could be vasoconstriction or induction of endothelial cell apoptosis (3). Inhibition of β-adrenoceptors has been suggested to have a negative impact on tumor development as well as a direct effect on endothelial cells by downregulation of angiogenesis factors such as vascular endothelial growth factor, matrix metalloproteinase-2, and matrix metalloproteinase-9 (4,5). A possible involvement of the β 2 -adrenoceptor/cyclic adenosine monophosphate pathway has been described in tumor vascularization of glioblastoma (4).IH is the most frequent benign tumor of early childhood that shows specific biological features: after an initial phase of proliferation during the first year of life, a long-lasting period of spontaneous regression over several years is observed (6). The underlying molecular mechanism could not be completely determined because of a lack of models for IH. Until recently, neither IH cell lines nor animal models were available. Endothelial cells from IH show specific expression of glucos...

Identification of Serum Regression Signs in Infantile Hemangioma

“…In the involuting phase, reduction of the vascular lesions occurs; diseased vessel undergoes vasoconstriction leading to a slow progressive regression. Propanolol, a non-selective inhibitor of ß(1)- and ß(2)-adrenoceptor, is known to show a good therapeutic effect [8], [9], likely due, at least in part, to its ability to induce such vasoconstriction. In small babies vessel reduction occurring during the IH involuting phase may give a significant reduction of the vascular bed, relevant as compared to the body mass, with a consequent blood-concentration.…”

“…IH arises from multipotent stem cells leading to endothelial cells in the proliferating phase and to adipocytes during the involution/involuted phase and molecular mechanisms underlying hemangioma onset and involution are only partially defined [8]. Messenger RNA level of β-adrenoceptor has been indicated as possibly involved and such level may represent a potential molecular marker useful to discriminate IH from other vascular malformations [9]. Furthermore, Glucose transporter-1 (Glut-1) may also represent an useful diagnostic marker [10].…”

Propranolol Promotes Accelerated and Dysregulated Adipogenesis in Hemangioma Stem Cells

“…4,10,12,13,14,15 Recently, we have shown that propranolol also affects HemSCs, causing accelerated adipogenesis. In the absence of adipogenic induction, propranolol increased proadipogenic gene expression in HemSCs as early as 24 hours after starting treatment.…”

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.…”