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

Abstract

ALK1 belongs to the type I receptor family for transforming growth factor-␤ 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 physiologic ALK1 ligand remains controversial. In cultured endothelial cells, ALK1 and another TGF-␤ type I receptor, ALK5, regulate angiogenesis by controlling TGF-␤ 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 IntroductionHereditary hemorrhagic telangiectasia (HHT) is an autosomaldominant vascular disorder characterized by recurrent nosebleeds, mucocutaneous telangiectases, and arteriovenous malformations (AVMs) in the brain, lungs, liver, and gastrointestinal tract. 1,2 It has been shown that heterozygous mutations in ENDOGLIN (ENG) and Activin receptor-like kinase 1 (ALK1) cause HHT1 and HHT2, respectively. 2-4 Both of these genes are expressed predominantly in endothelial cells. 5,6 Because ENG and ALK1 are transforming growth factor-␤ (TGF-␤) type III and type I receptors, respectively, it has been postulated that HHT is caused by impaired signaling of a common TGF-␤ family ligand that interacts with these 2 receptors. Recent finding of mutations in the common downstream mediator of TGF-␤ family signals, SMAD4, in a subset of HHT patients also support this hypothesis. 7 Despite the identification of these genes responsible for HHT, the underlying mechanisms for the pathogenesis of HHT remain obscure. One of the chief contributing factors underlying this obscurity is the complexity of the transduction pathway of ENG, ALK1, and SMAD4. The TGF-␤ superfamily consists of more than 40 ligands that can be classified into several subfamilies, including TGF-␤, Activin, and bone morphogenetic protein (BMP). 8 TGF-␤ family cytokines exert their effects by binding to heteromeric complexes of 2 types of transmembrane serine/threonine kinase receptors. 9 The type II receptors function primarily as the binding receptors. On binding their ligand(s), type II receptors associate with and phosphorylate the type I receptors, which in turn activate downstream SMAD proteins. Each TGF-␤ ligand interacts with one or more type II and type I receptors, but TGFBR2 is the only type II receptor that has been shown to interact with TGF-␤ subfamily ligands (TGF-␤1, -␤2, and -␤3).ENG can interact with multiple TGF-␤ family members, such as TGF-␤1/␤3, Activin-A, BMP2, and BMP7, in the presence of a suitable ligand-binding type II...

Neonatal Hyperoxia Causes Pulmonary Vascular Disease and Shortens Life Span in Aging Mice

“…52 Although endothelial cellspecific ablation of Alk-1 in mice recapitulates HHT, loss of TGF-␤ receptor Alk-5 or the TGF-␤ type II receptor does not. 53 This suggests that loss of Alk-1 contributes to HHT via a TGF-␤-independent manner. But like people with mutations in BMPR-II, the incidence of HHT seen in heterozygous endoglin mice or in people with mutant Alk-1 or endoglin varies in age and degree.…”

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

“…Transgenic mice confirm that the mutations cause HHT, since some mice carrying one normal and one null copy of the respective gene (i.e. endoglin +/-or ACVRL1 +/-heterozygote mice) display features of HHT 151,[153][154][155] .…”

“…The most recent models indicate a return to TGF-ß1 rather than BMP9/10 causality in HHT 31 . Which ligand-receptor complexes contribute to HHT pathogenesis however, remains the subject of intense research 151,152 . This is likely to be clarified as other HHT disease genes are identified.…”

Maladie de Rendu-Osler

“…Dans ce même modèle, les cellules mononucléées circulantes issues de patients HHT1 avaient une moindre capacité de stimulation de la régénération du muscle cardiaque ischémié que des cellules provenant de donneurs sains. Plus récemment, l'invalidation ciblée d'Alk1, d'Alk5 ou TbR2 dans les cellules endothéliales a été réalisée en utilisant une recombinase Cre sous contrôle du promoteur d'Alk1 [20]. Les souris invalidées pour Alk1 ont un phénotype vasculaire marqué, contrairement aux souris invalidées pour Alk5 ou TbR2.…”