PUBLICATION

Deficiency in hereditary hemorrhagic telangiectasia-associated Endoglin elicits hypoxia-driven heart failure in zebrafish

Authors
Lelièvre, E., Bureau, C., Bordat, Y., Frétaud, M., Langevin, C., Jopling, C., Kissa, K.
ID
ZDB-PUB-230602-39
Date
2023
Source
Disease models & mechanisms   16(5): (Journal)
Registered Authors
Jopling, Chris, Kissa-Marin, Karima, Langevin, Christelle, Lelievre, Etienne
Keywords
Cardiomegaly, Endoglin, Endothelial cells, HHT, Heart failure, Hypoxia
MeSH Terms
  • Heart Failure*/metabolism
  • Endothelial Cells/metabolism
  • Animals
  • Telangiectasia, Hereditary Hemorrhagic*/complications
  • Telangiectasia, Hereditary Hemorrhagic*/genetics
  • Endoglin/genetics
  • Endoglin/metabolism
  • Activin Receptors, Type II/genetics
  • Zebrafish
(all 9)
PubMed
37264878 Full text @ Dis. Model. Mech.
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease caused by mutations affecting components of bone morphogenetic protein (BMP)/transforming growth factor-β (TGF-β) signaling in endothelial cells. This disorder is characterized by arteriovenous malformations that are prone to rupture, and the ensuing hemorrhages are responsible for iron-deficiency anemia. Along with activin receptor-like kinase (ALK1), mutations in endoglin are associated with the vast majority of HHT cases. In this study, we characterized the zebrafish endoglin locus and demonstrated that it produces two phylogenetically conserved protein isoforms. Functional analysis of a CRISPR/Cas9 zebrafish endoglin mutant revealed that Endoglin deficiency is lethal during the course from juvenile stage to adulthood. Endoglin-deficient zebrafish develop cardiomegaly, resulting in heart failure and hypochromic anemia, which both stem from chronic hypoxia. endoglin mutant zebrafish display structural alterations of the developing gills and underlying vascular network that coincide with hypoxia. Finally, phenylhydrazine treatment demonstrated that lowering hematocrit/blood viscosity alleviates heart failure and enhances the survival of Endoglin-deficient fish. Overall, our data link Endoglin deficiency to heart failure and establish zebrafish as a valuable HHT model.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
ABchemical treatment by environment: phenylhydrazineDays 21-29
engump11/+ (AB)standard conditionsDays 45-89
engump11/+ (AB)standard conditionsAdult
engump11/+; ko05Tg; la116Tg (AB)standard conditionsDays 45-89
engump11/+; ko05Tg; la116Tg (AB)standard conditionsAdult
engump11/+; ko05Tg; la116Tg (AB)standard conditionsAdult
engump11/+; ump12Tg (AB)standard conditionsDays 45-89
engump11/+; ump12Tg (AB)standard conditionsAdult
engump11/+; ump13Tg (AB)standard conditionsDays 45-89
engump11/+; ump13Tg (AB)standard conditionsAdult
1 - 10 of 73
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hu5333TgTransgenic Insertion
    ko05TgTransgenic Insertion
      la116TgTransgenic Insertion
        twu34TgTransgenic Insertion
          ump11
            		Indel
            ump12TgTransgenic Insertion
              ump13TgTransgenic Insertion
                1 - 7 of 7
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                Human Disease / Model
                Human Disease Fish Conditions Evidence
                hereditary hemorrhagic telangiectasiaTAS
                1 - 1 of 1
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                Sequence Targeting Reagents
                Target Reagent Reagent Type
                engCRISPR1-engCRISPR
                1 - 1 of 1
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                Fish
                Fish
                AB
                engump11/+ (AB)
                engump11/+; ko05Tg; la116Tg (AB)
                engump11/+; ump12Tg (AB)
                engump11/+; ump13Tg (AB)
                engump11/ump11 (AB)
                engump11/ump11; hu5333Tg; la116Tg (AB)
                engump11/ump11; ko05Tg; la116Tg (AB)
                engump11/ump11; twu34Tg (AB)
                engump11/ump11; ump12Tg (AB)
                1 - 10 of 15
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                Antibodies
                No data available
                Orthology
                No data available
                Engineered Foreign Genes
                Marker Marker Type Name
                EGFPEFGEGFP
                GFPEFGGFP
                mRFPEFGmRFP
                RFPEFGRFP
                1 - 4 of 4
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                Mapping
                No data available
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                Citation
                Lelièvre, E., Bureau, C., Bordat, Y., Frétaud, M., Langevin, C., Jopling, C., Kissa, K. (2023) Deficiency in hereditary hemorrhagic telangiectasia-associated Endoglin elicits hypoxia-driven heart failure in zebrafish. Disease models & mechanisms. 16(5):.