Mechanisms of Endothelial Cell Maturation and Vascular Quiescence in Infantile Hemangioma
General Genetics and Functional Genome Biology
Dermatology
Pediatric and Adolescent Medicine
Cell Biology
Final Report Abstract
Infantile hemangiomas are the most common benign vascular tumor of infancy and occur in 4-5% of mature neonates. The β-adrenergic receptor antagonists propranolol and atenolol are current therapies for complicated infantile hemangioma but concerning side effects can occur. Potentially concerning side effects are due to their antagonistic effect on β-adrenergic receptors and consist of sleep disorders, bronchospasm, bradycardia, hypotension and hypoglycemia. Propranolol and atenolol, as well as many other β-blockers, exist as a racemic mixture of R(+) and S(-) enantiomers, with the R(+) enantiomer mostly devoid of βblocker activity. It has been shown previously that R(+) propranolol inhibits in vitro endothelial differentiation of hemangioma-derived stem cells, likely through disruption of the transcription factor SOX18 activity. In my research I mainly investigated the effect of the R(+) enantiomers of propranolol and atenolol on the formation, in vivo, of infantile hemangioma-like blood vessels from hemangioma-derived stem cells. A murine xenograft model for infantile hemangioma vasculogenesis was used to test the effect of propranolol, atenolol and their R(+) enantiomers on infantile hemangioma vessel formation. Human vessels were verified by anti-human CD31 staining; pericyte coverage was determined by anti-⍺ smooth muscle actin staining. In addition, I analyzed the drugs for in vitro effects on endothelial and pericytic differentiation of hemangioma-derived stem cells. The R(+) enantiomers of the nonselective β-blocker propranolol and β1-selective antagonist atenolol significantly inhibited hemangioma-derived stem cell vessel formation in vivo. In vitro, atenolol and its R(+) enantiomer inhibited hemangiomaderived stem cell-to-endothelial differentiation in a manner similar to R(+) propranolol. The R(+) enantiomers had no effect on hemangioma-derived stem cell-to-pericyte differentiation. In summary, my experiments showed the R(+) enantiomers of propranolol and atenolol, which lack β-blocker activity, are sufficient to inhibit infantile hemangioma vasculogenesis in vivo, hemangioma stem cell-to-endothelial differentiation in vitro, supporting a non-β-adrenergic receptor-dependent mechanism. The R(+) enantiomer of propranolol was shown to cross the blood-brain barrier to a lesser degree than propranolol and its S(-) enantiomer. This, together with our findings suggests the R(+) enantiomers could be used at half the dose of the racemic β-adrenergic receptor antagonists to provide effective and safer treatment for endangering infantile hemangioma. These are promising results as propranolol (HEMANGEOL®) has been approved by the U.S. Food and Drug Administration (FDA) and the German Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) since 2014 for the treatment of infantile hemangioma. Therefore, the safety profile of the drug is well established. Using the R(+) enantiomer in the treatment of infantile hemangioma will potentially alleviate side effects and increase the current response rate of 60% of propranolol, without exposing children to higher propranolol doses or possibly to less-studied drugs with unknown potential risks.
Publications
- Diagnostik und Behandlung der hereditären hämorrhagischen Teleangiektasie [Diagnostic Criteria and Treatment of Hereditary Hemorrhagic Telangiectasia]. Laryngorhinootologie. 2020 Oct;99(10):682-693
Seebauer CT, Kuehnel T, Uller W, Bohr C, Andorfer KE
(See online at https://doi.org/10.1055/a-1220-7045) - Routine - Restaging after Primary nonsurgical Treatment of Laryngeal Squamous Cell Carcinoma – a Review. Strahlentherapie und Onkologie. 2020
Seebauer CT, Hackenberg B, Grosse J, Rennert J, Jung EM, Hautmann M, Ugele I, Michaelides I, Mehanna H, Bohr C, Künzel J
(See online at https://doi.org/10.1007/s00066-020-01706-9)
