Article

ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood

Department of Physiology and Functional Genomics, University of Florida College of Medicine, Shands Cancer Center, Gainesville 32610, USA.
Blood (Impact Factor: 10.45). 02/2008; 111(2):633-42. DOI: 10.1182/blood-2007-08-107359
Source: PubMed

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.

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Available from: Sung Park, Dec 11, 2015
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    • "during development (Park et al., 2008). Alk1-Cre is active at early stages of brain angiogenesis, as revealed by intercrosses with the Rosa26-loxSTOPlox-lacZ reporter strain (Figure 1B). "
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    • "flox/flox (Proctor et al., 2005), Itgb8 −/− (Zhu et al., 2002;Arnold et al., 2012), Pdgfb ret/ret (Abramsson et al., 2003), Tgfb1 −/− (Arnold et al., 2012), Tgfb3 −/− (Proetzel et al., 1995), Tgfbr2 flox/flox (Levéen et al., 2002), Tgfbr1/Alk5 flox/flox (Larsson et al., 2001), Tgfbr1/Alk1 flox/flox (Park et al., 2008), nesCre (nesCre8) (Petersen et al., 2002) and endothelial cell-specific PdgfbiCreER TM2 mice (Claxton et al., 2008) have been described. To induce Cre activity, we administered 200 μl tamoxifen (15 mg/ml in corn oil) by oral gavage of pregnant dams for two days before embryo harvest. "
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    • "Alk1 is primarily expressed in the endothelial cells (ECs) of the arterial vessels [20]. We have previously demonstrated that conditional deletion of the Alk1 gene in ECs is sufficient for the development of AVMs in the lung, brain, and GI tract, indicating that ALK1 expression and function in ECs are crucial for HHT pathogenesis [21], [22]. "
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