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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.


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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.


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