Deficiency in HHT-associated Endoglin elicits hypoxia-driven congestive heart failure in zebrafish.

Hereditary hemorrhagic Telangiectasia (HHT) is a rare genetic disease caused by mutations affecting components of Bone Morphogenetic Protein and Transforming Growth Factor-β (BMP/TGF-β) signaling in endothelial cells. This disorder is characterized by arterio-venous malformations which 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 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 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. Furthermore, 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 survival of Endoglin deficient fish.