PUBLICATION

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

Authors

Snodgrass, R.O., Govindpani, K., Plant, K., Kugler, E.C., Doh, C., Dawson, T., McCormack, L.E., Arthur, H.M., Chico, T.J.A.

ID

ZDB-PUB-230303-39

Date

2023

Source

Disease models & mechanisms 16(4): (Journal)

Registered Authors

Chico, Tim J.

Keywords

Angiogenesis, Endoglin, HHT, VEGF, Zebrafish

MeSH Terms

Mutation/genetics
Mitogen-Activated Protein Kinase Kinases/genetics
Activin Receptors, Type II/genetics
TOR Serine-Threonine Kinases
Animals
Endoglin/genetics
Vascular Endothelial Growth Factor A/genetics
Arteriovenous Malformations*/genetics
Zebrafish/metabolism
Telangiectasia, Hereditary Hemorrhagic*/drug therapy
Telangiectasia, Hereditary Hemorrhagic*/genetics

(all 11)

PubMed

36861761 Full text @ Dis. Model. Mech.

Abstract

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 develop 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 TOR or MEK pathways prevented abnormal trunk and cerebral vasculature phenotypes, while inhibiting NOS or MAPK pathways had no effect. Combined subtherapeutic TOR and MEK inhibition prevented vascular abnormalities, confirming synergy between these pathways in HHT. These results indicate the HHT-like phenotype in zebrafish endoglin mutants can be mitigated through modulation of VEGF signalling. Combined low dose MEK and TOR pathway inhibition may represent a novel therapeutic strategy in HHT.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
mCherry	eng^mu130/mu130; s916Tg	control	Protruding-mouth	brain vasculature plasma membrane	IFL	Fig. 3.
mCherry	eng^mu130/mu130; s916Tg	chemical treatment by environment: tivozanib	Protruding-mouth	brain vasculature plasma membrane	IFL	Fig. 3.
mCherry	eng^mu130/mu130; s916Tg	chemical treatment by environment: sirolimus	Protruding-mouth	brain vasculature plasma membrane	IFL	Fig. 4.
mCherry	eng^mu130/mu130; s916Tg	chemical treatment by environment: PD 0325901	Protruding-mouth	brain vasculature plasma membrane	IFL	Fig. 4.
mCherry	eng^mu130/mu130; s916Tg	control	Protruding-mouth	brain vasculature plasma membrane	IFL	Fig. 4.
mCherry	eng^mu130/mu130; s916Tg	standard conditions	Protruding-mouth	brain vasculature plasma membrane	IFL	Fig. 2.
mCherry	eng^mu130/mu130; s916Tg	control	Protruding-mouth	dorsal aorta plasma membrane	IFL	Fig. 3.
mCherry	eng^mu130/mu130; s916Tg	chemical treatment by environment: tivozanib	Protruding-mouth	dorsal aorta plasma membrane	IFL	Fig. 3.
mCherry	eng^mu130/mu130; s916Tg	chemical treatment by environment: PD 0325901	Protruding-mouth	dorsal aorta plasma membrane	IFL	Fig. 4.
mCherry	eng^mu130/mu130; s916Tg	control	Protruding-mouth	dorsal aorta plasma membrane	IFL	Fig. 4.

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
eng^mu130/mu130	standard conditions	Adult	heart increased size, abnormal	Fig. 1.
eng^mu130/mu130	standard conditions	Adult	integument vasculature hemorrhagic, abnormal	Fig. 1.
eng^mu130/mu130	standard conditions	Adult	whole organism decreased size, abnormal	Fig. 1.
eng^mu130/mu130; s916Tg	control	Protruding-mouth	basilar artery increased diameter, abnormal	Fig. 3.
eng^mu130/mu130; s916Tg	control	Protruding-mouth	brain vasculature blood vessel endothelial cell has extra parts of type blood vessel endothelial cell plasma membrane bounded cell projection, abnormal	Fig. 5.
eng^mu130/mu130; s916Tg	control	Protruding-mouth	brain vasculature blood vessel endothelial cell has extra parts of type blood vessel endothelial cell plasma membrane bounded cell projection, abnormal	Fig. 4.
eng^mu130/mu130; s916Tg	control	Protruding-mouth	brain vasculature blood vessel endothelial cell has extra parts of type blood vessel endothelial cell plasma membrane bounded cell projection, abnormal	Fig. 3.
eng^mu130/mu130; s916Tg	control	Protruding-mouth	dorsal aorta increased diameter, abnormal	Fig. 5.
eng^mu130/mu130; s916Tg	control	Protruding-mouth	dorsal aorta increased diameter, abnormal	Fig. 4.
eng^mu130/mu130; s916Tg	control	Protruding-mouth	dorsal aorta increased diameter, abnormal	Fig. 3.

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
mu130		Small Deletion	eng
s843Tg	Tg(kdrl:EGFP)	Transgenic Insertion
s916Tg	Tg(kdrl:Hsa.HRAS-mCherry)	Transgenic Insertion
y7Tg	Tg(fli1:nEGFP)	Transgenic Insertion

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
hereditary hemorrhagic telangiectasia	eng^mu130/mu130; s916Tg	standard conditions	TAS

Sequence Targeting Reagents

Fish

Fish
eng^mu130/mu130
eng^mu130/mu130; s916Tg
s916Tg

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
mCherry	EFG	mCherry

Mapping

Snodgrass et al., 2023 ZDB-PUB-230303-39 PMID:36861761

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

Snodgrass et al., 2023

ZDB-PUB-230303-39
PMID:36861761