Harvard Catalyst Profiles

Infantile hemangioma (IH) is an extraordinary example of vascular overgrowth wherein vessels form rapidly, 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. REcently, 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, R+ propranolol and R+ atenolol, along with a SOX18 small molecule inhibitor (Sm4), blocked hemangioma vessel formation in a pre-clinical model that uses IH patient derived HemSC. Our findings elucidate a novel etiological component of IH and validate a molecular target. Using R+ propranolol as a molecular probe, we uncovered by transcriptional profiling that the most coordinately decreased biological process during R (+) propranolol-mediated blockage HemSC endothelial differentiation is the mevalonate pathway. Furthermore, statins, which inhibit the rate limiting step in the mevalonate pathway, inhibit HemSC vessel formation in vivo. From this new data, we propose an entirely novel SOX18-mevalonate pathway axis as a central regulatory process in IH-vascular overgrowth. Our goals are to decipher how the SOX18-mevalonate pathway contributes to IH, investigate the gene regulatory networks that govern the vasculogenic and adipogenic transitions, and determine whether the SOX18-mevalonate axis is an etiological component in other vascular anomalies (VA), which could lead to further drug repurposing.

This project focuses on the capillary malformations (CM) that characterize Sturge-Weber syndrome (SWS), a rare neurocutaneous disorder in which CMs ? made up of enlarged capillary-like vessels - occur in the skin (sometimes called ?port-wine stain?), the leptomeninges and in the choroid of the eye. SWS patients suffer from neurological defects and glaucoma, as well as disfigurement from CMs on the face, and unfortunately, medical therapies for CMs do not exist and there is no cure. The 2013 discovery of a somatic activating mutation in GNAQ (p.R183Q) in SWS and non-syndromic CMs set the stage for molecular studies. GNAQ encodes Gαq, the α-subunit of the heterotrimeric Gq protein that activates phospholipase Cβ. Our lab showed the GNAQ R183Q allele is enriched in endothelial cells (EC) sorted from CM specimens. We have created cellular and mouse models to elucidate how the GNAQ mutation affects EC function, how these alterations lead to CM, and how we can prevent the formation or growth of CM. Although the mutation is enriched in EC, our goal is to identify the breadth of cell types that carry the somatic GNAQ R183Q allele. We also aim to develop more refined models of CM in mice and zebrafish to use as platforms for testing candidate drugs. On the molecular level, we are deeply investigating the role of protein kinase C (PKC) and angiopoietin-2 (ANGPT2) as downstream effectors of the constitutively active, mutant Gαq. These projects will help us better understand the pathophysiology of CM and hopefully lead to strategies to minimize the myriad of difficulties CM pose for patients with both non-syndromic and SWS CMs.

We study endothelial to mesenchymal transition (EndMT) in response to pathological conditions. One aspect of this work has centered on EndMT in the mitral valve after myocardial infarction. From this we serendipitously discovered that CD45, a well-known pan-leukocyte marker that has a protein tyrosine phosphatase activity, is expressed in valve endothelial cells undergoing EndMT and that the phosphatase activity is required for EndMT. In a recently published study (Nasim et al, ATVB 2023) we show that CD45 is sufficient to drive EndMT in human endothelial cells. Our current focus is to study the role of CD45 and EndMT in in atherosclerosis using mouse models in collaboration with Hong Chen's lab. Our long term goal is to identify ways to modulate EndMT in cardiovascular disease in order to prevent fibrosis and tissue stiffening.