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Therapeutic targeting of vascular malformation in a zebrafish model of hereditary haemorrhagic telangiectasia

Lookup NU author(s): Professor Helen ArthurORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023. Published by The Company of Biologists Ltd.Hereditary haemorrhagic telangiectasia (HHT) causes arteriovenous malformations (AVMs) in multiple organs to cause bleeding, neurological and other complications. HHT is caused by mutations in the BMP co-receptor endoglin. We characterised a range of vascular phenotypes in embryonic and adult endoglin mutant zebrafish and the effect of inhibiting different pathways downstream of Vegf signalling. Adult endoglin mutant zebrafish developed skin AVMs, retinal vascular abnormalities and cardiac enlargement. Embryonic endoglin mutants developed an enlarged basilar artery (similar to the previously described enlarged aorta and cardinal vein) and larger numbers of endothelial membrane cysts (kugeln) on cerebral vessels. Vegf inhibition prevented these embryonic phenotypes, leading us to investigate specific Vegf signalling pathways. Inhibiting mTOR or MEK pathways prevented abnormal trunk and cerebral vasculature phenotypes, whereas inhibiting Nos or Mapk pathways had no effect. Combined subtherapeutic mTOR and MEK inhibition prevented vascular abnormalities, confirming synergy between these pathways in HHT. These results indicate that the HHT-like phenotype in zebrafish endoglin mutants can be mitigated through modulation of Vegf signalling. Combined low-dose MEK and mTOR pathway inhibition could represent a novel therapeutic strategy in HHT.

Publication metadata

Author(s): Snodgrass RO, Govindpani K, Plant K, Kugler EC, Doh C, Dawson T, McCormack LE, Arthur HM, Chico TJA

Publication type: Article

Publication status: Published

Journal: Disease Models & Mechanisms

Year: 2023

Volume: 16

Issue: 4

Print publication date: 01/04/2023

Online publication date: 30/03/2023

Acceptance date: 27/02/2023

Date deposited: 26/06/2023

ISSN (print): 1754-8403

ISSN (electronic): 1754-8411

Publisher: The Company of Biologists Ltd.


DOI: 10.1242/dmm.049567

PubMed id: 36861761


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Funder referenceFunder name
PG/18/57/33941British Heart Foundation
the Medical Research Council Discovery Medicine North (DiMeN) Doctoral Training Partnership