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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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Submitted August 16, 2007
Accepted September 24, 2007
ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2 (HHT2)
Sung Ok Park, Young Jae Lee, Tsugio Seki, Kwon-Ho Hong, Naime Fliess, Zhigang Jiang, Alice Park, Xiaofang Wu, Vesa Kaartinen, Beth L. Roman, and S. Paul Oh*
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Shands Cancer Center, Gainesville, FL, United States
Department of Cell Biology, Georgetown University Medical Center, Washington, DC, United States
Developmental Biology Program, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, United States
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, United States
* Corresponding author; email: ohp{at}phys.med.ufl.edu.
ALK1 belongs to the type I receptor family for TGF- family ligands. Heterozygous ALK1 mutations cause hereditary hemorrhagic telangiectasia type 2 (HHT2), a multisystemic vascular disorder. Based largely on in vitro studies, TGF-1 has been considered as the most likely ALK1 ligand related to HHT, yet the identity of the physiological ALK1 ligand remains controversial. In cultured endothelial cells, ALK1 and another TGF- type I receptor, ALK5, regulate angiogenesis by controlling TGF- signal transduction, and that ALK5 is required for ALK1 signaling. However, the extent to which such interactions between these two receptors play a role in pathogenesis of HHT is unknown. Here 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 pathological features of HHT. On the other hand, 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- subfamily disease.
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