title: ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2.
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.
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Shands Cancer Center, Gainesville 32610, USA.
authors.forename: Sung O
authors.initials: SO
authors.lastname: Park
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Lee
authors.forename: Tsugio
authors.initials: T
authors.lastname: Seki
authors.forename: Kwon-Ho
authors.initials: KH
authors.lastname: Hong
authors.forename: Naime
authors.initials: N
authors.lastname: Fliess
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Jiang
authors.forename: Alice
authors.initials: A
authors.lastname: Park
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wu
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
authors.forename: Beth L
authors.initials: BL
authors.lastname: Roman
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II; D000818:Animals; D002460:Cell Line; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins
chemical_list: D008024:Ligands; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D029961:Zebrafish Proteins; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625842:Tgfbr1 protein, mouse