Non-β-Blocker Enantiomers of Propranolol and Atenolol Inhibit Vasculogenesis in Infantile Hemangioma

Propranolol and atenolol, current therapies for problematic infantile hemangioma (IH), are composed of R(+) and S(-) enantiomers: the R(+) enantiomer is largely devoid of beta-blocker activity. We show both R(+) propranolol and R(+) atenolol inhibit hemangioma stem cell (HemSC) to endothelial differentiation. Furthermore, both R(+) enantiomers inhibit the formation of IH-like blood vessels from HemSC in a murine xenograft model. As our previous work implicated the transcription factor SOX18 in propranolol-mediated inhibition of HemSC to endothelial differentiation, we tested a known SOX18 small molecule inhibitor (Sm4) and show that this compound inhibits HemSC vessel formation in vivo in a similar manner as the R(+) enantiomers. To uncover mechanism(s), we examined how R(+) propranolol alters SOX18 transcriptional activity. We show that R(+) propranolol directly interferes with SOX18 target gene trans-activation, disrupts SOX18-chromatin binding dynamics and reduces SOX18 dimer formation. With these new results, we propose that beta-blockers propranolol and atenolol may act independently of beta-adrenergic receptors and instead the mechanism of drug action for both propranolol and atenolol when used to treat IH includes R(+) enantiomer targeting of SOX18 transcriptional activity. The use of the R(+) enantiomers could increase safety and efficiency by reducing β1- and β2-related side effects in the treatment of infantile hemangioma and possibly in other types of vascular anomalies in which SOX18 plays a role

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Artikel online veröffentlicht:
24. Mai 2022