Description

Join us for a webinar with Joyce Bischoff, Ph.D., Professor of Surgery at Harvard Medical School/Boston Children's Hospital. She will present her talk entitled: “Cellular Drivers and Drug Mechanisms in Infantile Hemangioma."  

Abstract:   Infantile hemangioma (IH) is a benign vascular tumor that occurs in 5% of infants; in ~10% of cases, the vascular overgrowth causes severe problems for the infant.    Propranolol was discovered serendipitously to be effective for IH; despite its success, there is significant need for improved therapies because of side effects caused by its non-selective β-blocker activity.  We previously showed the R+ enantiomer of propranolol, which lacks β-blocker activity, inhibits hemangioma stem cell (HemSC) vessel formation in vivo and HemSC to endothelial differentiation in vitro via disruption of the transcription factor SOX18 - indicating a β-adrenergic independent mechanism for propranolol therapy in IH (Seebauer et al., JCI 2022).

In new experiments, we discovered R+ propranolol suppresses the mevalonate pathway in HemSC undergoing endothelial differentiation. The mevalonate pathway, central to cholesterol biosynthesis, is controlled by the rate-limiting enzyme 3 hydroxy-3-methylglutaryl-coenzyme A reductase. Confirming its functional requirement, simvastatin and atorvastatin inhibited HemSC vessel formation in vivo and HemSC endothelial differentiation in vitro. R+ propranolol inhibited maturation of SREBP-2, the master transcription factor for the mevalonate pathway genes and further, R+ propranolol reduced endogenous cholesterol levels in human ECs.  Sm4, a SOX18 inhibitor, showed similar results in these experiments.   

We propose an entirely novel SOX18-mevalonate pathway axis as a central regulatory process in IH-vascular overgrowth. This presents potentially new clinical research directions in which R+ propranolol and/or statins could be tested for efficacy in IH and other vascular anomalies in which SOX18 is expressed.