Harvard Catalyst Profiles

Infantile hemangioma (IH) is an extraordinary example of vascular overgrowth wherein vessels form rapidly, then undergo a slow spontaneous involution that leaves behind a fibrofatty residuum. IH is common: it occurs in 5% of infants, equating to ~183,200 infants/year in the U.S. alone. 10-15% of IH will cause complications – e.g. destroy facial structures and impair vision, breathing and feeding depending on the location. Propranolol was discovered serendipitously to be effective therapy for IH, yet some do not respond, regrowth occurs in ~20% of cases, and surgery is needed in 37% of patients to correct IH residua. REcently, we showed the non-beta blocker R+ enantiomers of propranolol and atenolol prevent hemangioma endothelial differentiation by directly interfering with the activity of the transcription factor SOX18 in hemangioma stem cells (HemSC). Further, R+ propranolol and R+ atenolol, along with a SOX18 small molecule inhibitor (Sm4), blocked hemangioma vessel formation in a pre-clinical model that uses IH patient derived HemSC. Our findings elucidate a novel etiological component of IH and validate a molecular target. Using R+ propranolol as a molecular probe, we uncovered by transcriptional profiling that the most coordinately decreased biological process during R (+) propranolol-mediated blockage HemSC endothelial differentiation is the mevalonate pathway. Furthermore, statins, which inhibit the rate limiting step in the mevalonate pathway, inhibit HemSC vessel formation in vivo. From this new data, we propose an entirely novel SOX18-mevalonate pathway axis as a central regulatory process in IH-vascular overgrowth. Our goals are to decipher how the SOX18-mevalonate pathway contributes to IH, investigate the gene regulatory networks that govern the vasculogenic and adipogenic transitions, and determine whether the SOX18-mevalonate axis is an etiological component in other vascular anomalies (VA), which could lead to further drug repurposing.