# Blood vessel assembly from multipotent hemangioma-derived stem cells

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $754,352

## Abstract

Abstract
Infantile hemangioma (IH) is an extraordinary example of vascular overgrowth wherein vessels
form rapidly over a year, 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. In the current
funding cycle, 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 we showed that R+
propranolol and R+ atenolol, along with the small molecule SOX18 inhibitor Sm4, block
hemangioma vessel formation in vivo in a pre-clinical model that uses IH patient derived
HemSC. Our findings elucidate a novel etiological component of IH and also validate a
molecular target, which opens new research directions for discovery and drug repurposing.
Using R-propranolol as a molecular probe, we uncovered by transcriptional profiling of HemSC
that the most decreased biological process during HemSC endothelial differentiation is the
mevalonate pathway. From this data, we propose an entirely novel SOX18-mevalonate
pathway axis as a central regulatory process that underpins IH-vascular overgrowth. We
suggest a new conceptual framework and clinical research directions in which R+ propranolol,
R+ atenolol, statins, or tipifarnib (all mevalonate pathway blockers) have the potential to be
repurposed to prevent vascular overgrowth. This molecular strategy should reduce side effects
seen with racemic (traditional) propranolol therapy due to beta-adrenergic receptor blockade
and provide rapid clinical benefit, especially for non-responder patients. Our goals in this
renewal are to decipher how the SOX18-mevalonate pathway contributes to IH formation and
investigate the gene regulatory networks that govern the vasculogenic and adipogenic
transitions. In addition, we aim to determine whether the SOX18-mevalonate axis is an
etiological component in other vascular anomalies (VA), which could lead to repurposing these
drugs to a wide range of VA.

## Key facts

- **NIH application ID:** 10891015
- **Project number:** 2R01HL096384-13
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Joyce E. Bischoff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $754,352
- **Award type:** 2
- **Project period:** 2009-04-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891015

## Citation

> US National Institutes of Health, RePORTER application 10891015, Blood vessel assembly from multipotent hemangioma-derived stem cells (2R01HL096384-13). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10891015. Licensed CC0.

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