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ResearchIn-Press PreviewAngiogenesisVascular biology Open Access | 10.1172/JCI179782

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

Annegret Holm,1 Matthew S. Graus,2 Jill Wylie-Sears,1 Jerry Wei Heng Tan,1 Maya Alvarez-Harmon,1 Luke Borgelt,1 Sana Nasim,1 Long Chung,2 Ashish Jain,3 Mingwei Sun,3 Liang Sun,3 Pascal Brouillard,4 Ramrada Lekwuttikarn,5 Yanfei Qi,2 Joyce Teng,5 Miikka Vikkula,4 Harry Kozakewich,6 John B. Mulliken,7 Mathias Francois,2 and Joyce Bischoff1

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Holm, A. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Graus, M. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Wylie-Sears, J. in: JCI | PubMed | Google Scholar |

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Tan, J. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Alvarez-Harmon, M. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Borgelt, L. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Nasim, S. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Chung, L. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Jain, A. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Sun, M. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Sun, L. in: JCI | PubMed | Google Scholar |

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Brouillard, P. in: JCI | PubMed | Google Scholar |

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Lekwuttikarn, R. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Qi, Y. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Teng, J. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Vikkula, M. in: JCI | PubMed | Google Scholar |

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Kozakewich, H. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Mulliken, J. in: JCI | PubMed | Google Scholar

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Francois, M. in: JCI | PubMed | Google Scholar |

1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

2The David Richmond Laboratory for Cardiovascular Development: Gene Regulati, The University of Sydney, Camperdown, Australia

3Research Computing, Information Technology, Boston Children’s Hospital, Boston, United States of America

4Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium

5Department of Dermatology, Lucile Packard Children’ Hospital at the Stanford University School of Medicine, Palo Alto, United States of America

6Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

7Department of Plastic and Oral Surgery, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America

Find articles by Bischoff, J. in: JCI | PubMed | Google Scholar |

Published February 25, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI179782.
Copyright © 2025, Holm et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 25, 2025 - Version history
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Abstract

Infantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis, and regression. Propranolol, the mainstay treatment, inhibits IH vessel formation via a β-adrenergic receptor independent off-target effect of its R(+) enantiomer on the endothelial SRY box transcription factor 18 (SOX18). Transcriptomic profiling of patient-derived hemangioma stem cells (HemSC) 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). AThe biological relevance of the endothelial SOX18-MVP axis in IH patient tissue was demonstrated by nuclear co-localization 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 novel 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-specific program may have therapeutic implications for other vascular disease entities involving pathological vasculogenesis and angiogenesis.

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  • Version 1 (February 25, 2025): In-Press Preview
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