ZFIN ID: ZDB-PUB-191213-6
BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance
Capasso, T.L., Li, B., Volek, H.J., Khalid, W., Rochon, E.R., Anbalagan, A., Herdman, C., Yost, H.J., Villanueva, F.S., Kim, K., Roman, B.L.
Date: 2019
Source: Angiogenesis   23(2): 203-220 (Journal)
Registered Authors: Roman, Beth, Yost, H. Joseph
Keywords: Bone morphogenetic protein, Hereditary hemorrhagic telangiectasia, Vascular development, Zebrafish
MeSH Terms:
  • Activin Receptors/genetics
  • Activin Receptors/metabolism*
  • Animals
  • Animals, Genetically Modified
  • Arteriovenous Malformations/genetics
  • Arteriovenous Malformations/metabolism
  • Arteriovenous Malformations/pathology
  • Blood Vessels/growth & development*
  • Blood Vessels/physiology*
  • Bone Morphogenetic Proteins/genetics
  • Bone Morphogenetic Proteins/physiology*
  • Cell Differentiation/genetics
  • Embryo, Nonmammalian
  • Endothelial Cells/physiology
  • Gene Expression Regulation, Developmental
  • Neovascularization, Physiologic/genetics*
  • Regeneration/genetics*
  • Signal Transduction/genetics
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Zebrafish Proteins/physiology
PubMed: 31828546 Full text @ Angiogenesis
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ABSTRACT
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular disorder characterized by development of high-flow arteriovenous malformations (AVMs) that can lead to stroke or high-output heart failure. HHT2 is caused by heterozygous mutations in ACVRL1, which encodes an endothelial cell bone morphogenetic protein (BMP) receptor, ALK1. BMP9 and BMP10 are established ALK1 ligands. However, the unique and overlapping roles of these ligands remain poorly understood. To define the physiologically relevant ALK1 ligand(s) required for vascular development and maintenance, we generated zebrafish harboring mutations in bmp9 and duplicate BMP10 paralogs, bmp10 and bmp10-like. bmp9 mutants survive to adulthood with no overt phenotype. In contrast, combined loss of bmp10 and bmp10-like results in embryonic lethal cranial AVMs indistinguishable from acvrl1 mutants. However, despite embryonic functional redundancy of bmp10 and bmp10-like, bmp10 encodes the only required Alk1 ligand in the juvenile-to-adult period. bmp10 mutants exhibit blood vessel abnormalities in anterior skin and liver, heart dysmorphology, and premature death, and vascular defects correlate with increased cardiac output. Together, our findings support a unique role for Bmp10 as a non-redundant Alk1 ligand required to maintain the post-embryonic vasculature and establish zebrafish bmp10 mutants as a model for AVM-associated high-output heart failure, which is an increasingly recognized complication of severe liver involvement in HHT2.
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