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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.
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.
URL: https://doi.org/10.1242/dmm.049567
DOI: 10.1242/dmm.049567
PubMed id: 36861761
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