An endothelial SOX18–mevalonate pathway axis enables repurposing of statins for infantile hemangioma
Annegret Holm, … , Mathias Francois, Joyce Bischoff
Annegret Holm, … , Mathias Francois, Joyce Bischoff
Published February 25, 2025
Citation Information: J Clin Invest. 2025;135(7):e179782. https://doi.org/10.1172/JCI179782.
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Research Article Angiogenesis Vascular biology

An endothelial SOX18–mevalonate pathway axis enables repurposing of statins for infantile hemangioma

Abstract

Infantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis, and regression. Propranolol, the mainstay of treatment, inhibits IH vessel formation via a β-adrenergic receptor-independent off-target effect of its R(+) enantiomer on endothelial SOX18 - a member of the SOX (SRY-related HMG-box) family of transcription factors. Transcriptomic profiling of patient-derived hemangioma stem cells uncovered the mevalonate pathway (MVP) as a target of R(+) propranolol. Loss and gain of function of SOX18 confirmed it is both necessary and sufficient for R(+) propranolol suppression of the MVP, including regulation of sterol regulatory element–binding protein 2 (SREBP2) and the rate-limiting enzyme HMG-CoA reductase (HMGCR). A biological relevance of the endothelial SOX18-MVP axis in IH patient tissue was demonstrated by nuclear colocalization of SOX18 and SREBP2. Functional validation in a preclinical IH xenograft model revealed that statins — competitive inhibitors of HMGCR — efficiently suppress IH vessel formation. We propose an endothelial SOX18-MVP axis as a central regulator of IH pathogenesis and suggest statin repurposing to treat IH. The pleiotropic effects of R(+) propranolol and statins along the SOX18-MVP axis to disable an endothelial cell–specific program may have therapeutic implications for other vascular disease entities involving pathological vasculogenesis and angiogenesis.

Authors

Annegret Holm, Matthew S. Graus, Jill Wylie-Sears, Jerry Wei Heng Tan, Maya Alvarez-Harmon, Luke Borgelt, Sana Nasim, Long Chung, Ashish Jain, Mingwei Sun, Liang Sun, Pascal Brouillard, Ramrada Lekwuttikarn, Yanfei Qi, Joyce Teng, Miikka Vikkula, Harry Kozakewich, John B. Mulliken, Mathias Francois, Joyce Bischoff

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Figure 1

R(+) propranolol reduces MVP transcripts in IH-derived HemSCs undergoing endothelial differentiation.

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R(+) propranolol reduces MVP transcripts in IH-derived HemSCs undergoing...
HemSCs in A–C were treated with or without R(+) propranolol for 2 hours before RNA isolation. (A) KEGG pathway analysis and Gene Ontology Biological Processes (GO-BP) analysis of bulk RNA-Seq data from HemSCs treated on day 6 of endothelial differentiation (n = 6 biological replicates) with or without R(+) propranolol, showing the number of differentially expressed genes (DEGs), defined as log2 fold change greater than 1 and adjusted P less than 0.05. (B) Heatmap of differentially expressed MVP genes at day 4 and day 6. (C) Volcano plots of DEGs on day 4 and day 6 of HemSC to HemEC differentiation (–log10 for adjusted P value). (D) SOX18 mRNA levels on day 4 and day 6 (n = 3 biological replicates; 1 of the biological replicates was analyzed in 2 independent experiments, yielding n = 4 data points). (E) HemSCs induced to undergo endothelial differentiation were treated with or without R(+) propranolol for 2 hours on day 6 or treated continuously from day 2 to day 6. qPCR analyses for HMGCS1, HMGCR, and MVK (n = 3 biological replicates; 1 of the biological replicates was analyzed in 2 independent experiments, yielding n = 4 data points). P values were calculated using a 2-tailed, unpaired t test (D) and by a 1-way ANOVA multiple-comparison test with Šidák correction (E). Data are shown as the mean ± SD.