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


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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    ABSTRACT: Vascular development of the central nervous system and blood-brain barrier (BBB) induction are closely linked processes. The role of factors that promote endothelial sprouting and vascular leak, such as vascular endothelial growth factor A, are well described, but the factors that suppress angiogenic sprouting and their impact on the BBB are poorly understood. Here, we show that integrin αVβ8 activates angiosuppressive TGFβ gradients in the brain, which inhibit endothelial cell sprouting. Loss of αVβ8 in the brain or downstream TGFβ1-TGFBR2-ALK5-Smad3 signaling in endothelial cells increases vascular sprouting, branching and proliferation, leading to vascular dysplasia and hemorrhage. Importantly, BBB function in Itgb8 mutants is intact during early stages of vascular dysgenesis before hemorrhage. By contrast, Pdgfb(ret/ret) mice, which exhibit severe BBB disruption and vascular leak due to pericyte deficiency, have comparatively normal vascular morphogenesis and do not exhibit brain hemorrhage. Our data therefore suggest that abnormal vascular sprouting and patterning, not BBB dysfunction, underlie developmental cerebral hemorrhage. © 2014. Published by The Company of Biologists Ltd.
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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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    ABSTRACT: Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic vascular disease in which arteriovenous malformations (AVMs) manifest in skin and multiple visceral organs. HHT is caused by heterozygous mutations in endoglin (ENG), activin receptor-like kinase 1 (ALK1), or SMAD4. ALK1 regulates angiogenesis, but the precise function of ALK1 in endothelial cells (ECs) remains elusive. Since most blood vessels of HHT patients do not produce pathological vascular lesions, ALK1 heterozygous ECs may be normal unless additional genetic or environmental stresses are imposed. To investigate the cellular and biochemical phenotypes of Alk1-null versus Alk1-heterozygous ECs, we have generated pulmonary EC lines in which a genotype switch from the Alk1-conditional allele (Alk1 (2f)) to the Alk1-null allele (Alk1 (1f)) can be induced by tamoxifen treatment. Alk1-null (1 f/1 f) ECs displayed increased migratory properties in vitro in response to bFGF compared with Alk1-het (2 f/1 f) ECs. The 1 f/1 f-ECs formed a denser and more persistent tubular network as compared with their parental 2 f/1 f-ECs. Interestingly, the response to BMP-9 on SMAD1/5 phosphorylation was impaired in both 2 f/1 f- and 1 f/1 f-ECs at a comparable manner, suggesting that other factors in addition to SMADs may play a crucial role for enhanced angiogenic activity in 1 f/1 f-ECs. We also demonstrated in vivo that Alk1-deficient ECs exhibited high migratory and invasive properties. Taken together, these data suggest that enhanced responses to angiogenic cues in ALK1-deficient ECs underlie the pathogenesis of HHT2.
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