大象传媒

Speaker:听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鈥檚 Hospital.

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

Time: September 24 at 14.30.

Place: Webinar through Zoom.听
Link to join Webinar:
Webinar ID: 628 4148 6301
Webinar Passcode: g2LKt2Ht

Chair: Reidunn Edelmann

Abstract:

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

Infantile hemangioma (IH) has a unique lifecycle in which vascular听overgrowth occurs for over the first 6-9 months of infancy, followed by听a slow spontaneous involution of blood vessels over several years.听 For听most children, IH does not pose a serious threat and therapy is听unnecessary; however, in about 10% of cases, IH can enlarge听dramatically, threaten organs and cause permanent disfigurement. Over听the last 10 years, propranolol, a well-known non-selective 尾-adrenergic听receptor antagonist, has emerged as first-line therapy for endangering听IH, yet how and why it works so well in reducing the vascular overgrowth听in IH has remained a mystery.听 There is a significant need to improve听propranolol therapy because up to 18% of IHs fail to respond, up to 25%听resume growth when the drug is stopped, and 37% of propranolol-treated听infants require surgery at 5-6 years of age to minimize deformity caused听by remaining fibrofatty residua. To improve on propranolol, it is听essential to elucidate it鈥檚 mechanism of action against vascular听overgrowth, which will then provide a path forward to advance IH medical听therapy, and potentially other neovascular diseases as well.听听

We听previously identified a hemangioma stem cell (HemSC) from human IH听surgical specimens that can differentiate into endothelial cells,听pericytes and adipocytes and form hemangioma-like vessels within 7 days听when implanted into immune-deficient mice.听 Subsequent studies from our听lab and others validate HemSCs as the IH-initiating cell.听 Our recent听results show that a small molecule inhibitor of the transcription factor听SOX18 and propranolol both effectively block HemSC-to-endothelial听differentiation. Furthermore, the R(+) enantiomer of propranolol, which听lacks 尾-adrenergic receptor antagonistic activity, is equally effective.

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

Capillary malformation (CM), sometimes referred to as 鈥減ort-wine stain鈥�,听is the most common type of vascular malformation. CMs are composed of听enlarged capillary-like vessels just below the surface of the skin that听are seen at birth and over time can darken, form nodules, and cause听soft-tissue and skeletal overgrowth beneath the stain. Sturge-Weber听syndrome (SWS) is a neurocutaneous disorder associated with CMs of the听face, leptomeninges, and the choroid of the eye; patients suffer from听neurological defects and glaucoma. Drug treatment for CMs does not exist听and there is no cure. The 2013 discovery of a somatic activating听mutation in GNAQ (p.R183Q) in non-syndromic cutaneous CMs and SWS CMs听set the stage for molecular studies of this understudied vascular听malformation. GNAQ encodes G伪q, the 伪-subunit of the heterotrimeric Gq听protein that activates phospholipase C尾. We showed that the GNAQ R183Q听allele is enriched in the endothelial cell (EC) sorted from cutaneous CM听and SWS brain specimens.听 We have developed cellular and mouse models to听elucidate how the GNAQ mutation affects EC function and leads to CM.听We've learned that human ECs with the R183Q mutation do not respond听properly to laminar shear stress, express increased levels of听angiopoietin-2 and form enlarged CM-like vessels when implanted into听mice.听 This later finding demonstrates that the GNAQ R183Q in听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鈥檚 Hospital.听 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.听听 Her current research is focused on stem cells that drive growth infantile hemangioma 鈥� a common vascular tumor that grows and regresses through early childhood.听 In addition, Dr. Bischoff is also investigating capillary malformation in Sturge-Weber Syndrome. A third focus is on endothelial plasticity in cardiac valves.听 听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. 听She has served on numerous NIH study sections including as a member of the Cardiovascular Differentiation and Development Study Section from 2004-2008.听 She was also elected to the Council (2005-2008) and then President (2015) of the North American Vascular Biology Organization (NAVBO).

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