title: Propranolol induces regression of hemangioma cells through HIF-1α-mediated inhibition of VEGF-A.
abstract: OBJECTIVE
  To investigate the mechanism of propranolol on regression of infantile hemangiomas.
  
  
  BACKGROUND
  Propranolol has been found to be effective in treatment of severe hemangiomas of infancy. However, its mechanism of action is as yet unknown.
  
  
  METHODS
  Cultured proliferating and involuting hemangioma endothelial cells were treated with varying concentrations of propranolol for up to 4 days. Analysis was performed using cell viability, migration, and tubulogenesis assays, as well as quantitative RT-PCR and flow cytometry. Western blots and ELISA assays were used to assess protein expression.
  
  
  RESULTS
  Treatment with propranolol led to a dose dependent cytotoxic effect in hemangioma endothelial cells with decreased cell viability, migration, and tubulogenesis. This cytotoxic effect was VEGF (vascular endothelial growth factor) dependent, as demonstrated by decreased VEGF, VEGF-R1, and VEGF-R2 production. Decreased signaling through the VEGF pathway resulted in downregulation of PI3/Akt and p38/MAPK activity. Decreased VEGF activity was mediated through the hypoxia inducible factor (HIF)-1α pathway but not through NF-κβ signaling.
  
  
  CONCLUSIONS
  Collectively, these data suggest that propranolol exerts its suppressive effects on hemangiomas through the HIF-1α-VEGF-A angiogenesis axis, with effects mediated through the PI3/Akt and p38/MAPK pathways. These findings provide a plausible mechanism of action of propranolol on regression of infantile hemangiomas.
authors.affiliation: Department of Plastic Surgery, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Harvey
authors.initials: H
authors.lastname: Chim
authors.forename: Bryan S
authors.initials: BS
authors.lastname: Armijo
authors.forename: Erin
authors.initials: E
authors.lastname: Miller
authors.forename: Christy
authors.initials: C
authors.lastname: Gliniak
authors.forename: Marc A
authors.initials: MA
authors.lastname: Serret
authors.forename: Arun K
authors.initials: AK
authors.lastname: Gosain
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D054443:Cell Migration Assays; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects*; D006391:Hemangioma / Q000188:drug therapy* / Q000503:physiopathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D011433:Propranolol / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000319:Adrenergic beta-Antagonists; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D014665:Vasodilator Agents; D011433:Propranolol