Infantile hemangiomas β3-adrenoceptor overexpression is associated with nonresponse to propranolol

Background: Propranolol (antagonist of β1-/β2-AR but minimally active against β3-AR) is currently the first-line treatment for infantile hemangiomas (IH). Its efficacy is attributed to the blockade of β2-AR. However, its success rate is ~60%. Considering the growing interest in the angiogenic role of β3-ARs, we evaluated a possible relationship between β3-AR expression and response to propranolol. Methods: Fifteen samples of surgical biopsies were collected from patients with IH. Three were taken precociously from infants and then successfully treated with propranolol (responder group). Twelve were taken later, from residual lesions noncompletely responsive to propranolol (nonresponder group). A morphometrical analysis of the percentage of β1-, β2-, and β3-ARs positively stained area was compared between the two groups. Results: While no difference was found in both β1- and β2-AR expression level, a statistically significant increase of β3-AR positively stained area was observed in the nonresponder group. Conclusions: Although the number of biopsies is insufficient to draw definitive conclusions, and the different β-AR pattern may be theoretically explained by the different timing of samplings, this study suggests a possible correlation between β3-AR expression and the reduced responsiveness to propranolol treatment. This study could pave the way for new therapeutic perspectives to manage IH. Impact: Propranolol (unselective antagonist of β1 and β2-ARs) is currently the first-line treatment for IHs, with a success rate of ~60%.Its effectiveness has been attributed to its ability to block β2-ARs.However, β3-ARs (on which propranolol is minimally active) were significantly more expressed in hemangioma biopsies taken from patients nonresponsive to propranolol.This study suggests a possible role of β3-ARs in hemangioma pathogenesis and a possible new therapeutic target.