Harvard Catalyst Profiles

Infantile hemangioma (IH) is a common vascular tumor with a unique lifecycle of rapid blood vessel formation over the first 6-9 months of infancy, followed by a slow spontaneous involution of blood vessels over several years. For most children, IH does not pose a serious threat and therapy is unnecessary; however, in about 10% of cases, IH can enlarge dramatically, threaten organs and cause permanent disfigurement. Over the last 10 years, propranolol, a well-known non-selective β-adrenergic receptor antagonist, has emerged as first-line therapy for endangering IH, yet how and why it works so well in reducing the vascular overgrowth in IH has remained a mystery. There is a significant need to improve propranolol therapy because up to 18% of IHs fail to respond, up to 25% resume growth when the drug is stopped, and 37% of propranolol-treated infants require surgery at 5-6 years of age to minimize deformity caused by remaining fibrofatty residua. To improve on propranolol therapy for IH, it is essential to elucidate its mechanism of action against vascular overgrowth in IH. Our lab identified a hemangioma stem cell (HemSC) from human IH surgical specimens that can form hemangioma-like vessels within 7 days when implanted into immune-deficient mice. Subsequent studies from our lab and others validate HemSCs as the IH-initiating cell. Our recent results show that a small molecule inhibitor of the transcription factor SOX18 called Sm4 and propranolol both effectively block HemSC-to-endothelial differentiation. Furthermore, the R(+) enantiomer of propranolol, which lacks β-adrenergic receptor antagonistic activity, is equally effective. R+ propranolol can disrupt SOX18 dimer formation in vitro. This novel discovery identifies a β-adrenergic receptor-independent, SOX18-dependent mechanism by which propranolol reduces vascular overgrowth in IH. We are pursuing this by testing the effect of R+ propranolol on IH vessel formation in vivo, investigating the dimerization status of SOX18 in IH and how propranolol and the R(+) enantiomer might alter SOX18-dependent transcription. In parallel, we are also investigating possible genetic contributors to IH, in particular chromosomal translocations or small copy number variants by deep coverage RNA-Seq on freshly isolated IH cells. We hypothesis that genetic abnormalities may alter SOX18 dimerization and its ability to regulate transcription needed to control vascular growth.

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.