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Bischoff Laboratory Research | Overview

We study 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. 

Our recent work is focused on mechanisms of drug action. Propranolol was discovered serendipitously to be effective therapy for IH yet its mechanism of action has been unclear. We showed the non-beta blocker R+ enantiomer of propranolol prevents HemSC differentiation and blood vessel formation in vivo by interfering with the transcription factor SOX18. Our most recent work, posted on bioRvix, shows that R+ enantiomer of propranolol suppresses the mevalonate pathway, needed for cholesterol and isoprenoid biosynthesis. We next showed that statins, which inhibit the rate-limiting enzyme in the mevalonate pathway, inhibit HemSC endothelial differentiation and blood vessel formation in vivo.  In summary, our recent findings elucidate a novel etiological component of IH and open new research directions for discovery and drug repurposing. 

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, enriched in endothelial cells of CMs, is found in 90% of non-syndromic and syndromic 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 CM are present at birth and progress over time to cause significant morbidity.

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.