Abstract
ALK1 belongs to the type I receptor family for transforming growth factor-beta family ligands. Heterozygous ALK1 mutations cause hereditary hemorrhagic telangiectasia type 2 (HHT2), a multisystemic vascular disorder. Based largely on in vitro studies, TGF-beta1 has been considered as the most likely ALK1 ligand related to HHT, yet the identity of the physiologic ALK1 ligand remains controversial. In cultured endothelial cells, ALK1 and another TGF-beta type I receptor, ALK5, regulate angiogenesis by controlling TGF-beta signal transduction, and ALK5 is required for ALK1 signaling. However, the extent to which such interactions between these 2 receptors play a role in pathogenesis of HHT is unknown. We directly addressed these issues in vivo by comparing the phenotypes of mice in which the Alk1, Alk5, or Tgfbr2 gene was conditionally deleted in restricted vascular endothelia using a novel endothelial Cre transgenic line. Alk1-conditional deletion resulted in severe vascular malformations mimicking all pathologic features of HHT. Yet Alk5- or Tgfbr2-conditional deletion in mice, or Alk5 inhibition in zebrafish, did not affect vessel morphogenesis. These data indicate that neither ALK5 nor TGFBR2 is required for ALK1 signaling pertinent to the pathogenesis of HHT and suggest that HHT might not be a TGF-beta subfamily disease.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Activin Receptors, Type I / genetics
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Activin Receptors, Type I / metabolism*
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Activin Receptors, Type II
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Animals
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Cell Line
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Endothelium, Vascular / metabolism
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Endothelium, Vascular / pathology
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Ligands
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Mice
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Mice, Knockout
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism*
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Neovascularization, Pathologic / pathology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism*
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Signal Transduction* / genetics
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Telangiectasia, Hereditary Hemorrhagic / genetics
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Telangiectasia, Hereditary Hemorrhagic / metabolism*
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Telangiectasia, Hereditary Hemorrhagic / pathology
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / metabolism
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Zebrafish / genetics
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Zebrafish / metabolism
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Zebrafish Proteins
Substances
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Ligands
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Receptors, Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Zebrafish Proteins
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Protein Serine-Threonine Kinases
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Activin Receptors, Type I
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Activin Receptors, Type II
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Acvrl1 protein, mouse
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Tgfbr1 protein, mouse