Endoglin deficiency elicits hypoxia-driven congestive heart failure in zebrafish

Abstract Hereditary hemorrhagic Telangiectasia (HHT) is a rare genetic disease relying on mutations affecting components of Bone Morphogenetic Protein and Transforming Growth Factor-β (BMP/TGF-β) signaling pathway in endothelial cells. This disorder is characterized by arterio-venous malformations prone to rupture. and ensuing hemorrhages are responsible for iron deficiency anemia. Along with Activin receptor-like kinase ALK1, Endoglin is involved in the vast majority of HHT cases. In this report, we characterized zebrafish endoglin locus and demonstrated that it produces two phylogenetically conserved protein isoforms using a distinctive alternative splicing mechanism. Functional analysis of a Crispr/Cas9 zebrafish Endoglin mutant revealed that Endoglin deficiency results in massive death during the course from juvenile stage to adulthood. Endoglin deficient fish develop a cardiomegaly resulting in heart failure and hypochromic anemia which both stem from chronic hypoxia. Histological analysis and confocal imaging evidenced structural alterations of the developing gill and its underlying vascular network that tally with hypoxia. Finally, phenylhydrazine treatment demonstrated that lowering hematocrit/blood viscosity alleviates heart failure and enhances survival of Endoglin deficient fish. Altogether, our data indicate that Endoglin is crucial for gill vascular development and that further studies using zebrafish in general and this endoglin mutant in particular will provide crucial hints regarding the molecular and cellular events altered in HHT for the development of new therapeutic strategies. Summary Statement Endoglin deficiency in zebrafish recapitulates critical aspects of Hereditary Hemorrhagic Telangiectasia (HHT) and will thus constitute a valuable model in large scale screens for HHT-active drugs.