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Blood, 15 January 2008, Vol. 111, No. 2, pp. 633-642. Prepublished online as a Blood First Edition Paper on October 2, 2007; DOI 10.1182/blood-2007-08-107359. This Article Full Text Full Text (PDF) Supplemental Methods, References and Figures All Versions of this Article: blood-2007-08-107359v1 111/2/633    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Park, S. O. Articles by Oh, S. P. PubMed PubMed Citation Articles by Park, S. O. Articles by Oh, S. P. Related Collections Signal Transduction Hemostasis, Thrombosis, and Vascular Biology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2 Sung O. Park1, Young Jae Lee1, Tsugio Seki1, Kwon-Ho Hong1, Naime Fliess1, Zhigang Jiang1, Alice Park2, Xiaofang Wu2, Vesa Kaartinen3, Beth L. Roman2,4, and S. Paul Oh1 1 Department of Physiology and Functional Genomics, University of Florida College of Medicine, Shands Cancer Center, Gainesville, FL; 2 Department of Cell Biology, Georgetown University Medical Center, Washington, DC; 3 Developmental Biology Program, Children's Hospital Los Angeles, University of Southern California, Los Angeles; and 4 Department of Biologic Sciences, University of Pittsburgh, PA ALK1 belongs to the type I receptor family for transforming growth factor-β family ligands. Heterozygous ALK1 mutations cause hereditary hemorrhagic telangiectasia type 2 (HHT2), a multisystemic vascular disorder. Based largely on in vitro studies, TGF-β1 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-β type I receptor, ALK5, regulate angiogenesis by controlling TGF-β 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-β subfamily disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: HHT is not a TGFβ disease Sabine Bailly Blood 2008 111: 478. [Full Text] [PDF] This article has been cited by other articles: M. T. Holderfield and C. C.W. Hughes Crosstalk Between Vascular Endothelial Growth Factor, Notch, and Transforming Growth Factor-{beta} in Vascular Morphogenesis Circ. Res., March 28, 2008; 102(6): 637 - 652. [Abstract] [Full Text] [PDF]

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