High levels of β2‐adrenoceptors are expressed in infantile capillary hemangiomas and may mediate the therapeutic effect of propranolol

To the Editor, Infantile capillary hemangiomas are tumors of endothelium with small vascular lumina and a lobated configuration. Although benign in nature, they may cause disfigurement and hemorrhage, and therefore patients with proliferative hemangiomas are referred for treatment. In 2008, propranolol was been introduced as a new systemic treatment option for infantile capillary hemangiomas and has shown convincing results to date.1 Propranolol is a well-known competitive, nonselective β-adrenergic antagonist. However, the mechanism of action in hemangiomas has not yet been elucidated. β2-Adrenoceptors are known to be the dominating adrenergic receptors on peripheral vessel endothelium.2 Infantile hemangiomas treated with propranolol regularly pass through different stages of involution: they turn brighter and softer, then they stop to grow within months and finally regress.2 It was hypothesized that these phenomena are caused by vasoconstriction, inhibition of angiogenesis and induction of apoptosis. All of these mechanisms are mediated by the inhibition of β2adrenoceptors by propranolol. The aim of this study was to analyze the expression and localization of β2adrenoceptors in infantile capillary hemangiomas in comparison to senile hemangiomas to further elucidate the mechanism of action of propranolol in the treatment of hemangiomas. Therefore we examine the expression of β2-adrenoceptors in infantile hemangiomas by immunohistochemical staining and compare the expression pattern with senile hemangiomas. The average age of the patients at the time of hemangioma surgery was 2.6 months (range: 2–12 months). None of the patients was on medication with beta blockers. Localizations of hemangiomas were head, trunk and upper extremities (data not shown). The average age of the patients with senile hemangiomas was 52.9 (range: 15–87 years). Diagnosis of infantile hemangiomas was confirmed by positive staining for glucose transporter 1 (Glut-1)3 in all cases (Fig. 1F). Both infantile and senile hemangiomas express β2-adrenoceptors (Fig. 1A–D), the isotype control was negative, indicating that staining was specific (Fig. 1E). However, infantile hemangiomas show a stronger staining for β2-adrenoceptors in comparison to senile hemangiomas (Fig. 1A–D). In both tumor entities staining was mainly detectable on endothelial cells of the vascular proliferates (Fig. 1). This finding was confirmed by CD31 and CD34 staining in several infantile hemangiomas (data not shown). To quantitatively compare the expression of β2adrenoceptors in both tumor entities, samples were stained and evaluated using the scoring system as described in the figure legend. All samples were additionally evaluated by hematoxylin and eosin staining (H&E) and several hemangiomas were exemplarily stained with CD31 and CD34 in parallel to differentiate endothelial cells from connective tissue cells. Representative examples for the different staining intensities in infantile hemangiomas are shown in Fig. 2. We found a significant difference in staining scores between infantile and senile hemangiomas (Fig. 2D). Infantile capillary hemangiomas express high levels of β2-adrenoceptors, which