An endothelial SOX18–mevalonate pathway axis enables repurposing of statins for infantile hemangioma
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
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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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 4

Nuclear colocalization of SOX18 and SREBP2 in IH and congenital vascular tumors.

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Nuclear colocalization of SOX18 and SREBP2 in IH and congenital vascular...
(A–D) Human age-matched skin, proliferating IH, involuting IH, and regrowing IH stained with anti-SREBP2 (magenta), anti-SOX18 (cyan), and the human endothelial cell–specific lectin UEA1 (yellow). Cell nuclei stained with DAPI (blue). (E and F) Rapidly involuting and non-involuting congenital hemangiomas (RICH and NICH) stained in the same manner. Boxed areas are shown enlarged in the bottom panels. (G) SOX18+SREBP2+ double-positive cell nuclei (arrowheads) were quantified and expressed relative to total endothelial cells. P values were calculated using 1-way ANOVA with Šidák correction. Data are shown as the mean ± SD. Data represent 15 representative images each for patient sample sizes n = 4 for age-matched skin controls, n = 10 each for proliferating- and involuting-phase IH, n = 4 for regrowing IH, and n = 3 each for RICH and NICH. See Table 1 for detailed patient information. Scale bars: 50 μm (top panels) and 25 μm (bottom magnified panels).