The Bischoff Lab studies cellular and molecular mechanisms that drive vascular tumors and vascular malformations.

The specific type of vascular tumor we focus on is called infantile hemangioma (IH), a unique tumor that grows rapidly during infancy, forming a vascular overgrowth, and then undergoes spontaneous involution. Several years ago, we identified an undifferentiated vascular stem cell in proliferating IH — hemangioma stem cells (HemSC) — that differentiate into endothelial cells and mural cells, and form blood vessels in immune-deficient mice. In summary, we showed IH is formed at least in part by HemSC undergoing de novo blood vessel formation.

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In 2008, propranolol was discovered serendipitously by clinicians in France to be effective therapy for IH, yet its mechanism of action has been unclear. Propranolol is a racemic 1:1 mixture of two enantiomers. The S-enantiomer exerts the well-known “beta-blocker activity,” while the R+ enantiomer is devoid of beta-blocker activity. This provides an experimental opportunity to test the requirement for beta-blocker activity for treating IH. We found the R+ enantiomer of propranolol efficiently blocks HemSC differentiation and IH blood vessel formation in vivo by interfering with the transcription factor SOX18. Our most recent work shows that R+ enantiomer of propranolol suppresses the mevalonate pathway, needed for cholesterol and isoprenoid biosynthesis. To interrogate the importance of this SOX18-mevalonate pathway axis, we showed that statins, which inhibit the rate-limiting enzyme in the mevalonate pathway, inhibit HemSC endothelial differentiation and IH blood vessel formation in vivo. In summary, our recent findings elucidate a novel etiological component of IH, open new research directions for discovery and potential to repurpose statins.

The vascular malformation we focus on is called capillary malformation (CM). CMs are composed of enlarged and tortuous capillary-venule-sized blood vessels with abnormal flow. A somatic activating mutant in GNAQ, which codes for the α-subunit of the heterotrimeric G-protein Gαq, the GNAQ p.R183Q mutation, found in 90 percent of non-syndromic and syndromic CMs, is enriched in endothelial cells of CMs. Non-syndromic, cutaneous CM are known as port wine birthmarks. In Sturge-Weber syndrome (SWS), CM are found in the leptomeninges of the brain, the choroid of the eye, and skin, in a distinctive facial pattern. The CM on the skin can cause tissue overgrowth, and CM in the brain leptomeninges can lead to debilitating seizures, hemiparesis, and migraines. Both types of CM are present at birth and progress over time to cause significant morbidity.

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We set out to determine how the GNAQ R183Q mutation causes CM, using cellular and xenograft models with GNAQ R183Q endothelial cells. We showed the R183Q mutant endothelial cells form CM-like vessels in immune-deficient mice and identified angiopoietin2 (ANGPT2) as an important driver of the CM phenotype. Our current work is focused on how the somatic mosaicism of GNAQ R183Q in endothelial cells causes the cellular defects seen in CMs, such as reduced endothelial barrier formation, increased sprouting, and increased macrophage adhesion. We are also focused on understanding the broad impacts of the mutant GNAQ on endothelial signaling and functions, and identifying drugs that can reverse or mitigate the causative abnormalities.

This adjacent image shows lack of claudin-5 (magenta), a tight junction protein, in some of the CM vessels (Nasim et al, Angiogenesis, 2024).

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