CCBIO Seminar – Joyce Bischoff

Speaker: Joyce Bischoff, Professor of Surgery at Harvard Medical School with a primary appointment in the Vascular Biology Program and Department of Surgery at Boston Children’s Hospital.

Topic of the talk: "Endothelial Anomalies in Vascular Tumors and Vascular Malformations." 

Time: September 24 at 14.30.

Place: Webinar through Zoom. 
Link to join Webinar: https://uib.zoom.us/j/62841486301?pwd=ZGFLUnNZUmw4VklURGRxd2VxbWtFZz09
Webinar ID: 628 4148 6301
Webinar Passcode: g2LKt2Ht

Chair: Reidunn Edelmann

Abstract:

The seminar will cover two topics: 1) the common vascular tumor of infancy known as infantile hemangioma and 2) capillary malformations in the setting of Sturge-Weber syndrome, a rare neurocutaneous disorder.

Infantile hemangioma (IH) has a unique lifecycle in which vascular overgrowth occurs for 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, it is essential to elucidate it’s mechanism of action against vascular overgrowth, which will then provide a path forward to advance IH medical therapy, and potentially other neovascular diseases as well.  

We previously identified a hemangioma stem cell (HemSC) from human IH surgical specimens that can differentiate into endothelial cells, pericytes and adipocytes and 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 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.

This novel discovery identifies a β-adrenergic receptor-independent, SOX18-dependent mechanism by which propranolol reduces vascular overgrowth in IH.

Capillary malformation (CM), sometimes referred to as “port-wine stain”, is the most common type of vascular malformation. CMs are composed of enlarged capillary-like vessels just below the surface of the skin that are seen at birth and over time can darken, form nodules, and cause soft-tissue and skeletal overgrowth beneath the stain. Sturge-Weber syndrome (SWS) is a neurocutaneous disorder associated with CMs of the face, leptomeninges, and the choroid of the eye; patients suffer from neurological defects and glaucoma. Drug treatment for CMs does not exist and there is no cure. The 2013 discovery of a somatic activating mutation in GNAQ (p.R183Q) in non-syndromic cutaneous CMs and SWS CMs set the stage for molecular studies of this understudied vascular malformation. GNAQ encodes Gαq, the α-subunit of the heterotrimeric Gq protein that activates phospholipase Cβ. We showed that the GNAQ R183Q allele is enriched in the endothelial cell (EC) sorted from cutaneous CM and SWS brain specimens.  We have developed cellular and mouse models to elucidate how the GNAQ mutation affects EC function and leads to CM. We've learned that human ECs with the R183Q mutation do not respond properly to laminar shear stress, express increased levels of angiopoietin-2 and form enlarged CM-like vessels when implanted into mice.  This later finding demonstrates that the GNAQ R183Q in endothelial cells is sufficient to form vessels reminiscent of CM.

Short bio:

Dr. Bischoff is Professor of Surgery at Harvard Medical School with a primary appointment in the Vascular Biology Program and Department of Surgery at Boston Children’s Hospital.  She received an A.B. in Chemistry from Duke University, a Ph.D. in Biochemistry and Molecular Biology from Washington University School of Medicine in St. Louis and post-doctoral training at the Whitehead Institute for Biomedical Research in Cambridge, MA.   Her current research is focused on stem cells that drive growth infantile hemangioma – a common vascular tumor that grows and regresses through early childhood.  In addition, Dr. Bischoff is also investigating capillary malformation in Sturge-Weber Syndrome. A third focus is on endothelial plasticity in cardiac valves.   Dr. Bischoff is currently serving as co-Editor-in-Chief of Angiogenesis, and also serves on the editorial boards of Journal of Clinical Investigation, Circulation Research, Blood and ATVB.  She has served on numerous NIH study sections including as a member of the Cardiovascular Differentiation and Development Study Section from 2004-2008.  She was also elected to the Council (2005-2008) and then President (2015) of the North American Vascular Biology Organization (NAVBO).