TARGETS OF PROPRANOLOL IN INFANTILE HEMANGIOMA

Abstract

Infantile hemangioma (IH) is a vascular neoplasm that affects 4–10 percent of infants. Propranolol, a non‐selective β‐adrenergic receptor (AR) antagonist, was serendipitously discovered to accelerate regression of IH in 2008; however, its mechanism in IH is unclear. In this study, β1,2 ‐ARs were found expressed in IH tissues by qPCR. “Wrinkle assay” detected that wrinkles formed by hemangioma pericytes (Hem‐Pericytes) relaxed in response to epinephrine, but this was strongly inhibited if propranolol was added before epinephrine. These responses were blunted by silencing the β2‐AR with siRNA. Propranolol had no effect on the contractility of placental or retinal pericytes in this assay. Propranolol also blocked proliferation of Hem‐Pericytes, but not hemangioma‐derived endothelial (HemECs) or stem cells (HemSCs). HemECs and Hem‐Pericytes suspended in Matrigel were implanted in mice. At 7 days, vascular perfusion of the cell/Matrigel implants was verified; mice were divided into two groups and treated with vehicle or propranolol for 7 days. Contrast‐enhanced micro‐ultrasonography of the implants showed a significantly decreased blood flow in propranolol‐treated animals, but no reduction in those treated with vehicle. These experiments identified Hem‐Pericytes and β2‐AR as likely targets of propranolol. Supported by NIH P01 AR48564.