Affinage

ACVRL1

Activin receptor type-1-like · UniProt P37023

Length
503 aa
Mass
56.1 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACVRL1 (ALK1) is an endothelial type I serine/threonine kinase receptor that transduces BMP9/BMP10 signals through Smad1/5 phosphorylation to control vascular morphogenesis, endothelial quiescence, and arterial caliber. ALK1 recognizes BMP9 and BMP10 as high-affinity ligands via a tripartite binding mechanism involving its β4-β5 loop, signals through caveolin-1-dependent endocytosis, and synergizes with Notch to repress tip cell formation and VEGF signaling; its activity is positively regulated by the adaptor SnoN and endoglin, and negatively regulated by Smad7/PP1α-mediated dephosphorylation and LUBAC-mediated linear ubiquitination (PMID:20124460, PMID:32238803, PMID:22421041, PMID:24019535, PMID:15385967, PMID:16571110, PMID:34157307, PMID:33097593). Beyond canonical BMP signaling, ALK1 mediates non-degradative LDL transcytosis across endothelium; arterial endothelial-specific ALK1 deletion reduces atherosclerotic plaque formation, and a monoclonal antibody selectively blocking LDL transcytosis without disrupting BMP9 signaling recapitulates this protection (PMID:27869117, PMID:39196046). Loss-of-function mutations in ACVRL1 cause hereditary hemorrhagic telangiectasia type 2 (HHT2), with somatic second-hit mutations driving focal arteriovenous malformations through a Knudsonian two-hit mechanism compounded by flow-dependent failure to limit arterial caliber (PMID:20501893, PMID:31630786, PMID:21389051).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1999 High

    Establishing ALK1 as a Smad1-specific kinase resolved which downstream effector this orphan receptor activated, revealing that specificity depends on the L45 loop and Smad1 MH2 domain surfaces distinct from canonical BMP receptors.

    Evidence In vitro kinase assays with L45 loop and MH2 domain mutagenesis

    PMID:9920917

    Open questions at the time
    • Endogenous ligands for ALK1 not yet identified
    • In vivo relevance of Smad1 specificity not demonstrated
  2. 1999 High

    Demonstrating that TGFβ activates ALK1 via the type II receptor TβRII and that endoglin participates in the complex identified ALK1 as a TGFβ superfamily receptor and explained why HHT mutations in both ALK1 and endoglin cause overlapping disease.

    Evidence Chimeric receptor signaling assays, co-immunoprecipitation, HHT missense mutation analysis

    PMID:10187774 PMID:10767348

    Open questions at the time
    • Whether TGFβ is the physiologically relevant ligand in vivo remained uncertain
    • Endoglin's precise role in promoting ALK1 vs. ALK5 signaling not yet defined
  3. 2002 High

    Genetic loss of alk1 in zebrafish produced dilated AVMs with excess endothelial cells, establishing for the first time that ALK1 restricts endothelial cell number and prevents arteriovenous shunting in vivo.

    Evidence Zebrafish alk1 mutant (violet beauregarde), endothelial cell counting, in situ hybridization

    PMID:12050147

    Open questions at the time
    • Mechanism by which ALK1 limits endothelial cell number unknown
    • Mammalian in vivo confirmation pending
  4. 2003 High

    Showing that ALK1 directly antagonizes ALK5/Smad2/3 signaling and requires ALK5 kinase activity for its own activation established the ALK1-ALK5 balance model governing endothelial proliferation versus quiescence.

    Evidence ALK5-deficient endothelial cells, reporter assays, co-immunoprecipitation

    PMID:14580334

    Open questions at the time
    • Whether the ALK5-dependence of ALK1 activation applies in all vascular beds not tested
  5. 2004 High

    Demonstrating that endoglin-null endothelial cells show impaired ALK1 signaling and enhanced ALK5 signaling resolved endoglin's function as a facilitator that biases TGFβ signaling toward the ALK1/Smad1/5 arm.

    Evidence Endoglin-deficient endothelial cells, Smad phosphorylation and proliferation assays

    PMID:15385967

    Open questions at the time
    • Structural basis for endoglin-ALK1 cooperation unknown
    • Whether endoglin is required for BMP9/10-ALK1 signaling not addressed
  6. 2006 High

    Identification of Smad7 and PP1α as negative regulators that dephosphorylate ALK1 defined the signal termination mechanism for the ALK1/Smad1/5 pathway.

    Evidence Co-immunoprecipitation, siRNA, phosphatase inhibition assays, reporter assays

    PMID:16571110

    Open questions at the time
    • In vivo relevance of PP1α-mediated ALK1 dephosphorylation not tested
  7. 2007 High

    Conditional endothelial Alk1 deletion in mice recapitulated HHT2 while Alk5 and Tgfbr2 deletion did not, overturning the model that ALK1 requires ALK5/TβRII in vivo and implying a distinct ligand drives ALK1 in endothelium.

    Evidence Conditional endothelial-specific KO mice (Alk1, Alk5, Tgfbr2), zebrafish ALK5 inhibition

    PMID:17911384

    Open questions at the time
    • The identity of the in vivo ALK1 ligand in endothelium remained unknown
  8. 2007 High

    Localization of ALK1 to caveolae and identification of a direct caveolin-1 interaction that enhances ALK1 signaling established the membrane microdomain required for ALK1 signal transduction.

    Evidence Confocal microscopy, co-immunoprecipitation with domain mapping, siRNA knockdown of caveolin-1

    PMID:18065769

    Open questions at the time
    • Whether caveolin-1 dependence extends to BMP9/10-specific ALK1 signaling not yet tested
  9. 2010 High

    A systematic screen of 29 TGFβ-family ligands identified BMP9 and BMP10 as the sole high-affinity ALK1 ligands, resolving a long-standing question about the physiological activators of ALK1 in endothelium.

    Evidence Surface plasmon resonance ligand screen, Id-1 reporter and Matrigel assays

    PMID:20124460

    Open questions at the time
    • Relative contributions of BMP9 vs. BMP10 in vivo unclear
    • Whether other ligands activate ALK1 in non-endothelial contexts not excluded
  10. 2010 High

    Systematic functional analysis of 19 HHT2 mutations showed most retain surface expression but lose BMP9 signaling without dominant-negative effects, supporting haploinsufficiency as the primary disease mechanism.

    Evidence Site-directed mutagenesis, BMP9 reporter and binding assays, surface expression quantification

    PMID:20501893

    Open questions at the time
    • Somatic second-hit mechanism not yet investigated
    • Earlier study found some kinase domain mutations with dominant-negative activity (PMID:16282348), creating unresolved discrepancy
  11. 2011 High

    Demonstrating that blood flow induces alk1 expression and that AVM progression is flow-dependent established ALK1 as a mechanosensitive transducer that converts hemodynamic force into a biochemical signal limiting arterial caliber.

    Evidence Zebrafish alk1 mutant with blood flow manipulation, endothelial cell counting

    PMID:21389051

    Open questions at the time
    • Molecular mechanism of flow-induced ALK1 expression unknown
    • Whether this applies to mammalian vasculature not directly shown
  12. 2012 High

    Showing that ALK1/Smad signaling synergizes with Notch to induce HEY1/HEY2 and repress tip cell formation unified two major pathways controlling angiogenic sprouting and explained why ALK1 loss causes hypersprouting.

    Evidence Postnatal mouse retinal assays, combined Notch/Alk1 blockade, BMP9 rescue

    PMID:22421041

    Open questions at the time
    • Direct physical interaction between ALK1-Smad and Notch pathways at chromatin level not demonstrated
  13. 2012 High

    NMR and crystal structures of the ALK1 extracellular domain and kinase domain provided the first atomic-level understanding of ALK1 architecture and revealed an unusual β4-β5 loop conformation requiring a rotated BMP9 binding mode.

    Evidence NMR and X-ray crystallography, SPR mutagenesis validation

    PMID:22799562 PMID:25557927

    Open questions at the time
    • Full ternary complex structure with type II receptor not available
  14. 2013 High

    Identification of cardiac BMP10 as the crucial circulating ALK1 ligand during embryonic vascular development, distributed by blood flow, connected ligand identity, hemodynamics, and ALK1 signaling into an integrated model of arterial caliber control.

    Evidence Zebrafish bmp10 loss-of-function, flow manipulation, alk1 expression rescue

    PMID:23863480

    Open questions at the time
    • Whether BMP9 serves a distinct postnatal role not resolved in this model
  15. 2013 High

    Discovery that SnoN directly binds ALK1 at the plasma membrane and facilitates Smad1/5 phosphorylation identified a previously unknown positive regulator whose disruption causes AVMs and embryonic lethality.

    Evidence Co-immunoprecipitation, Smad phosphorylation assays, genetic mouse model

    PMID:24019535

    Open questions at the time
    • Whether SnoN facilitates BMP9 vs. BMP10 signaling differentially is untested
  16. 2016 High

    A genome-wide RNAi screen identified ALK1 as a mediator of non-degradative LDL transcytosis in endothelial cells, revealing a signaling-independent function of ALK1 with direct relevance to cholesterol transport.

    Evidence Genome-wide RNAi screen, LDL binding/uptake/transcytosis assays, endothelial-specific Alk1 KO in Ldlr-KO mice

    PMID:27869117

    Open questions at the time
    • Structural basis for ALK1-LDL interaction unknown
    • Whether LDL transcytosis and BMP signaling can be pharmacologically separated not yet shown
  17. 2016 High

    Live imaging in alk1 mutant zebrafish revealed that ALK1 controls directed endothelial migration against blood flow rather than proliferation in lumenized arteries, refining the cellular mechanism of AVM formation.

    Evidence Live endothelial cell tracking in zebrafish alk1 mutants, proliferation quantification

    PMID:27287800

    Open questions at the time
    • Molecular mediators downstream of ALK1 that direct migration not identified
  18. 2018 High

    Demonstrating that ALK1 loss increases PI3K activity through reduced PTEN function, and that PI3K inhibition rescues ALK1-haploinsufficient vascular hyperplasia, identified a druggable effector pathway downstream of ALK1.

    Evidence ALK1+/- mice, retinal analysis, PI3K/PTEN signaling assays, pharmacological rescue, HHT2 patient biopsies

    PMID:29449337

    Open questions at the time
    • Mechanism by which Smad1/5 signaling activates PTEN not defined
  19. 2019 Medium

    Identification of somatic second-hit ACVRL1 mutations in HHT telangiectasia supported a Knudsonian two-hit model, explaining why vascular malformations are focal despite germline haploinsufficiency.

    Evidence Next-generation sequencing of 19 telangiectasia lesions, phasing of somatic and germline mutations

    PMID:31630786

    Open questions at the time
    • Only 9/19 lesions showed biallelic loss; alternative mechanisms in remaining lesions unknown
    • Independent replication in larger cohorts needed
  20. 2020 High

    Crystal structures of BMP10:ALK1 and prodomain-bound BMP9:ALK1 complexes defined the tripartite recognition mechanism for ligand specificity, explaining why only BMP9 and BMP10 activate ALK1.

    Evidence X-ray crystallography (2.3 and 3.3 Å), mutagenesis, SPR, cell signaling assays

    PMID:32238803

    Open questions at the time
    • Full hexameric complex with type II receptor and endoglin not structurally resolved
  21. 2020 High

    Showing that BMP9-triggered ALK1 internalization is caveolin-1/dynamin-2-dependent and competes with LDL transcytosis mechanistically linked ALK1's signaling and transport functions through shared endocytic machinery.

    Evidence Endocytosis assays with siRNA knockdown of CAV-1, DNM2, and clathrin; SMAD1/5 phosphorylation and LDL transcytosis quantification

    PMID:33097593

    Open questions at the time
    • Whether caveolar vs. endosomal ALK1 pools are functionally distinct in vivo is unclear
  22. 2021 High

    Discovery that LUBAC conjugates linear ubiquitin chains onto ALK1 to inhibit its kinase activity, reversed by OTULIN, identified a novel post-translational regulatory layer; HHT2-mutant ALK1 shows excessive linear ubiquitination, linking this mechanism directly to disease.

    Evidence EC-specific Otulin KO mice, ubiquitination assays, co-immunoprecipitation, constitutively active ALK1 rescue

    PMID:34157307

    Open questions at the time
    • Which specific lysine residues on ALK1 are ubiquitinated not mapped
    • Whether LUBAC/OTULIN regulation affects LDL transcytosis is unknown
  23. 2022 High

    Extending ALK1 function beyond endothelium, BMP9/BMP10/ALK1 signaling was shown to control Kupffer cell identity and self-renewal through Smad4, with ALK1 loss causing KC replacement by monocyte-derived macrophages and impaired pathogen capture.

    Evidence Macrophage/KC-specific Alk1 KO mice, flow cytometry, Listeria infection challenge

    PMID:34874921

    Open questions at the time
    • Downstream transcriptional targets of ALK1 in Kupffer cells not fully characterized
    • Whether this represents a direct cell-autonomous function or paracrine effect not fully excluded
  24. 2022 High

    Identification of FOXF1 and FLI1 as transcriptional activators of the ACVRL1 promoter, combined with in vivo demonstration that ACVRL1 silencing impairs neonatal lung angiogenesis, defined the upstream regulatory circuit controlling ALK1 expression in pulmonary endothelium.

    Evidence scRNA-seq, promoter reporter assays, nanoparticle siRNA in vivo knockdown, BMP9 rescue

    PMID:35440116

    Open questions at the time
    • Whether FOXF1-dependent regulation is specific to lung endothelium or generalizable is unknown
  25. 2022 High

    Hepatic endothelial ALK1 signaling through the BMP9/ALK1/ID axis was shown to regulate Wnt2 and R-spondin-3 expression, maintaining liver sinusoidal endothelial cell identity and metabolic zonation.

    Evidence LSEC-selective Acvrl1 KO mice, transcriptomics, ID function inhibition, HHT liver specimens

    PMID:35776660

    Open questions at the time
    • Whether ALK1 regulates Wnt signaling in other organ vasculatures is unexplored
  26. 2023 High

    A monoclonal antibody that selectively blocks ALK1-mediated LDL transcytosis without disrupting BMP9 signaling dramatically reduced atherosclerosis, demonstrating therapeutic separability of ALK1's dual functions.

    Evidence Endothelial-specific Alk1 KO mice, selective monoclonal antibody, plaque quantification in Ldlr-KO mice

    PMID:39196046

    Open questions at the time
    • Long-term vascular safety of selective LDL-transcytosis blockade not assessed
    • Structural epitope on ALK1 responsible for LDL binding versus BMP9 binding not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for ALK1-LDL interaction, how flow-sensing is molecularly transduced through ALK1, the full hexameric receptor complex structure with type II receptors, and whether the two-hit mechanism accounts for all HHT2 vascular malformations.
  • No structural model of ALK1-LDL binding interface
  • Mechanotransduction mechanism linking shear stress to ALK1 activation undefined
  • Complete receptor signaling complex structure not solved
  • Two-hit model only validated in ~50% of lesions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0038024 cargo receptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 3 R-HSA-382551 Transport of small molecules 3
Partners
CAV1ENGHOIPPPP1CASKILSMAD1SMAD5SMAD7
Complex memberships
BMP9/10-ALK1-BMPRII/ActRII signaling complexTGFβ/BMP receptor complex (ALK1-TβRII-endoglin)

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 ALK1 induces Smad1/5 phosphorylation in endothelial cells, leading to increased proliferation and migration, while acting as an antagonist of the ALK5/Smad2/3 pathway. ALK5 kinase activity is required for TGFβ-dependent recruitment of ALK1 into a TGFβ receptor complex and for optimal ALK1 activation. ALK1 directly antagonizes ALK5/Smad signaling. Endothelial cell signaling assays, loss-of-function (ALK5-deficient cells), reporter assays, co-immunoprecipitation Molecular cell High 14580334
1999 ALK1 specifically phosphorylates and activates Smad1. The specificity of Smad1 recognition by ALK1 requires both the receptor L45 loop and two surface structures on the Smad1 MH2 domain (L3 loop and alpha-helix 1), a mechanism distinct from that used by BMPR-I to activate Smad1. In vitro kinase assays, mutagenesis of L45 loop and Smad MH2 domain, specificity mapping The Journal of biological chemistry High 9920917
1999 TGFβ1 and TGFβ3, as well as an unidentified serum ligand, can activate ALK1 signaling. The ALK1/TGFβ interaction is mediated by the TGFβ type II receptor. Endoglin binds both ALK1 and TGFβ type I receptor. HHT-associated missense mutations in the ALK1 extracellular domain abrogate signaling. Chimeric receptor signaling assay (kinase domain swap), PAI-1 promoter reporter, co-immunoprecipitation, mutagenesis The Journal of biological chemistry High 10187774
2004 Endoglin is required for efficient TGFβ/ALK1 signaling; endothelial cells lacking endoglin show reduced ALK1 signaling and increased ALK5 signaling. Endoglin promotes endothelial cell proliferation by favoring the ALK1 pathway, which indirectly inhibits ALK5 signaling. Endoglin-deficient endothelial cells, reporter assays, cell proliferation assays, Smad phosphorylation The EMBO journal High 15385967
2002 Disruption of acvrl1 (alk1) in zebrafish results in increased endothelial cell number in specific cranial vessels, causing dilated arteriovenous malformations, establishing ALK1 as a TGFβ type I receptor essential for restricting endothelial cell number during vascular development. Zebrafish genetic mutant (violet beauregarde), in situ hybridization, endothelial cell counting Development (Cambridge, England) High 12050147
2010 Of 29 TGFβ-related ligands screened, only BMP9 and BMP10 display high-affinity binding to the ALK1 extracellular domain (ALK1-Fc). ALK1-Fc inhibits BMP9-mediated Id-1 expression in endothelial cells and inhibits cord formation on Matrigel. Surface plasmon resonance ligand screen, cell-based Id-1 reporter assay, Matrigel cord formation assay Molecular cancer therapeutics High 20124460
2007 Conditional endothelial deletion of Alk1 in mice produces severe vascular malformations mimicking all pathological features of HHT2, whereas conditional deletion of Alk5 or Tgfbr2 in endothelial cells (or Alk5 inhibition in zebrafish) does not affect vessel morphogenesis, demonstrating that ALK1's role in HHT pathogenesis is independent of ALK5 and TGFBR2 in vivo. Conditional endothelial-specific knockout mice (Alk1, Alk5, Tgfbr2), zebrafish Alk5 inhibition, vascular phenotype analysis Blood High 17911384
2012 ALK1 inhibits angiogenesis by synergizing with the Notch pathway in stalk cells. ALK1-dependent SMAD signaling synergizes with activated Notch to induce HEY1 and HEY2 expression, thereby repressing VEGF signaling, tip cell formation, and endothelial sprouting. BMP9 (high-affinity ALK1 ligand) rescues hypersprouting caused by Notch inhibition. Postnatal mouse retinal vascular assays, Notch/Alk1 combined blockade, BMP9 rescue, reporter assays in cultured endothelial cells Developmental cell High 22421041
2013 Cardiac-derived BMP10 is the crucial circulating ligand for endothelial ALK1 in embryonic vascular development. Blood flow promotes ALK1 activity by inducing alk1 expression and distributing BMP10, and together these limit endothelial cell number and stabilize nascent arterial caliber. Zebrafish bmp10 loss-of-function, alk1 expression rescue experiments, flow manipulation, endothelial cell quantification Development (Cambridge, England) High 23863480
2012 The crystal structure of the ALK1 intracellular kinase domain was determined. ALK1 mediates signaling via phosphorylation of SMAD1/5/8. A small molecule kinase inhibitor (K02288) inhibits BMP9-induced SMAD1/5/8 phosphorylation in endothelial cells and reduces both SMAD-dependent and Notch-dependent transcriptional responses. Crystal structure determination of ALK1 kinase domain, in vitro kinase inhibition assay, SMAD phosphorylation, reporter assays, endothelial sprouting assays Angiogenesis High 25557927
2020 Crystal structures of the BMP10:ALK1 complex (2.3 Å) and prodomain-bound BMP9:ALK1 complex (3.3 Å) revealed a tripartite recognition mechanism defining BMP9 and BMP10 specificity for ALK1. Introduction of BMP10-specific residues into BMP9 reduced signaling activity, validating the tripartite mechanism. X-ray crystallography, mutagenesis, C2C12 cell signaling assays, SPR Nature communications High 32238803
2012 NMR structure of the ALK1 extracellular domain determined; SPR identified residues in the β4-β5 loop critical for BMP9 binding. The altered conformation of the β4-β5 loop (compared to ALK3) necessitates a ~40° rotated binding mode for BMP9, with a large hydrophobic interface. NMR structure determination, SPR binding assays, mutagenesis Biochemistry High 22799562
2006 Smad7 and protein phosphatase 1α (PP1α) are critical determinants of the duration of TGFβ/ALK1 signaling. TGFβ/ALK1 upregulates Smad7 and PP1α; PP1α interacts with ALK1 and this association is potentiated by Smad7; PP1α dephosphorylates ALK1 to terminate Smad1/5 phosphorylation. siRNA knockdown, ectopic expression, co-immunoprecipitation, phosphatase inhibition assay, reporter assays BMC cell biology High 16571110
2016 ALK1 mediates LDL uptake and transcytosis in endothelial cells via an unusual non-degradative endocytic pathway. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. Endothelium-specific ablation of Alk1 in Ldlr-KO mice reduces LDL uptake into aortic endothelium. Genome-wide RNAi screen, LDL binding/uptake assays, transcytosis assays, endothelial-specific Alk1 KO mice Nature communications High 27869117
2023 Genetic deletion of ALK1 in arterial endothelial cells substantially limits LDL accumulation, macrophage infiltration, and atherosclerosis without affecting cholesterol levels. A selective monoclonal antibody blocking ALK1 LDL transcytosis (but not BMP9 signaling) dramatically reduces plaque formation in Ldlr-KO mice. Endothelial-specific Alk1 KO mice, monoclonal antibody blockade, atherosclerosis plaque quantification, LDL transcytosis assay Nature cardiovascular research High 39196046
2021 LUBAC conjugates linear ubiquitin chains onto ALK1, inhibiting its enzyme activity and Smad1/5 activation. OTULIN deubiquitinates ALK1 to promote Smad1/5 activation. EC-specific Otulin deletion causes arteriovenous malformations. HHT2 patient-derived mutant ALK1 exhibits excessive linear ubiquitination and increased HOIP binding. EC-specific Otulin KO mice, co-immunoprecipitation, ubiquitination assays, SMAD signaling assays, constitutively active ALK1 knockin rescue Molecular cell High 34157307
2007 ALK1 localizes to endothelial caveolae and physically interacts with caveolin-1 via the caveolin-1 scaffolding domain and the ALK1 caveolin-1 binding motif. Caveolin-1 enhances TGFβ/ALK1 signaling (opposite to its effect on ALK5). Caveolin-1 suppression abrogates ALK1 signaling. Confocal microscopy, cholesterol depletion, co-immunoprecipitation, domain mapping, ALK1-specific luciferase reporters, siRNA knockdown Cardiovascular research High 18065769
2002 Nuclear receptor LXRβ binds specifically to the cytoplasmic domain of ALK1 in vitro and in vivo. Activated ALK1 causes translocation of LXRβ from nucleus to cytoplasm, and ALK1 phosphorylates LXRβ primarily on serine residues. LXRβ subsequently inhibits ALK1- and ALK2-mediated transcriptional responses. In vitro binding assay, co-immunoprecipitation, subcellular fractionation, phosphorylation assay, transcriptional reporter assay The Journal of biological chemistry Medium 12393874
2013 SnoN binds directly to ALK1 on the plasma membrane upon ligand binding and facilitates the interaction between ALK1 and Smad1/5, enhancing Smad1/5 phosphorylation. Disruption of SnoN-Smad1/5 interaction impairs Smad1/5 activation, upregulates Smad2/3 activity, and causes arteriovenous malformations and embryonic lethality. Co-immunoprecipitation, plasma membrane binding assay, Smad phosphorylation assays, genetic mouse model with embryonic phenotype The Journal of cell biology High 24019535
2016 ALK1 controls arterial endothelial cell migration within lumenized vessels (rather than proliferation). In alk1-deficient zebrafish, migration against blood flow direction is dampened and migration in the direction of flow is enhanced, altering endothelial cell distribution and arterial caliber. Live imaging of zebrafish endothelial cells, cell tracking in alk1 mutants, proliferation assays Development (Cambridge, England) High 27287800
2014 Endothelial-specific depletion of Acvrl1 leads to venous enlargement, vascular hyperbranching, and arteriovenous malformations in neonatal retinal angiogenesis. Loss of Acvrl1 is associated with reduced arterial Jag1 expression, decreased pSmad1/5/8, and increased endothelial cell proliferation. Endoglin is markedly downregulated in Acvrl1-depleted endothelial cells, placing Endoglin downstream of Acvrl1 signaling. Endothelial-specific Acvrl1 conditional KO mice (neonatal and adult), retinal imaging, immunostaining, pSmad quantification PloS one High 24896812
2018 BMP9/ALK1 signaling represses VEGF-mediated PI3K activity by promoting PTEN activity. Loss of ALK1 function results in increased PI3K pathway activity and vascular hyperplasia. Pharmacological PI3K inhibition rescues vascular hyperplasia of ALK1+/- retinas. ALK1+/- heterozygous mice, retinal endothelial cell analysis, PI3K/PTEN signaling assays, pharmacological PI3K inhibition rescue, HHT2 patient biopsy analysis Arteriosclerosis, thrombosis, and vascular biology High 29449337
2020 BMP-9 binding to ALK-1 triggers extensive endocytosis of ALK1 mediated by caveolin-1 (CAV-1) and dynamin-2 but not clathrin. CAV-1 knockdown reduces BMP-9-mediated ALK1 internalization, BMP-9-dependent signaling, and gene expression. LDL reduces BMP-9-induced SMAD1/5 phosphorylation, and BMP-9-mediated ALK1 internalization strongly reduces LDL transcytosis. Endocytosis assays, siRNA knockdown (CAV-1, DNM2, clathrin), SMAD1/5 phosphorylation, LDL transcytosis assays The Journal of biological chemistry High 33097593
2010 Functional analysis of 19 ALK1 mutants reproducing HHT2 mutations showed that most are expressed and reach the cell surface but are defective in BMP9 signaling, while extracellular mutants lose BMP9 binding. None exhibit dominant-negative effects on wild-type ALK1 activity, supporting a haploinsufficiency model for HHT2. Site-directed mutagenesis, BMP9 signaling reporter assays, cell surface expression assays, BMP9 binding assays Blood High 20501893
2022 BMP9/BMP10/ALK1 signaling controls the identity and self-renewal of Kupffer cells (KCs) through a Smad4-dependent pathway. ALK1 is dispensable for macrophages in lung, kidney, spleen, and brain. ALK1 deletion causes KC loss over time, replaced by monocyte-derived macrophages with reduced VSIG4 expression, impairing Listeria monocytogenes capture. Macrophage/KC-specific Alk1 KO mice, flow cytometry, bacterial infection challenge, immunostaining The Journal of clinical investigation High 34874921
2022 FOXF1 transcription factor, acting synergistically with ETS factor FLI1, activates the ACVRL1 promoter. Loss of FOXF1 reduces BMP9/ACVRL1 signaling in pulmonary endothelial progenitor cells. Nanoparticle-mediated silencing of ACVRL1 in newborn mice decreases neonatal lung angiogenesis. BMP9 treatment restores lung angiogenesis in ACVRL1-deficient mice. scRNA-seq, ACVRL1 promoter reporter assays, FOXF1/FLI1 co-transfection, nanoparticle siRNA delivery KO in vivo, BMP9 rescue Nature communications High 35440116
2017 AMPK activation by metformin inhibits ALK1-mediated Smad1/5 phosphorylation and BMP9-induced tube formation. This is mediated by AMPK-induced upregulation of Smurf1, leading to degradation of ALK1 protein. Pharmacological AMPK activation, dominant-negative and constitutively-active AMPKα1 constructs, Smad1/5 phosphorylation assays, Smurf1 expression assays, Matrigel angiogenesis assay Oncotarget Medium 28427181
2011 Alk1 expression in arterial endothelial cells requires blood flow. In alk1-deficient zebrafish, initial increases in endothelial cell number are independent of blood flow, but later increases and AVM development are flow-dependent. Alk1 transduces hemodynamic forces into a biochemical signal limiting nascent arterial caliber. Zebrafish alk1 mutant analysis, blood flow manipulation, flow-responsive gene expression analysis, endothelial cell counting Development (Cambridge, England) High 21389051
2000 In COS-1 cells, ALK1 is found in TGFβ1 and TGFβ3 receptor complexes in association with endoglin and TβRII. In HUVEC, ALK1 and endoglin interact directly by co-immunoprecipitation in the absence of ligand, forming a transient association. Co-immunoprecipitation, immunoprecipitation/western blot in HUVEC and COS-1 cells, novel anti-ALK1 polyclonal antibody Human molecular genetics Medium 10767348
2013 In chondrocytes, BMP9 potently induces pSmad1/5 phosphorylation and a hypertrophy-like state (bAlpl, bColX expression). BMP9-induced Smad1/5 activation and hypertrophy markers are antagonized by TGFβ1. Primary bovine chondrocyte cultures, BMP9 stimulation, Western blot (pSmad), qPCR, reporter assay Osteoarthritis and cartilage Medium 25681563
2019 Somatic mutations resulting in bi-allelic loss of ACVRL1 (in trans with germline mutation) were identified in 9/19 HHT telangiectasia by next-generation sequencing, supporting a Knudsonian two-hit mechanism for focal vascular malformation development rather than haploinsufficiency alone. Next-generation sequencing of telangiectasia tissue, phase determination of somatic/germline mutations American journal of human genetics Medium 31630786
2013 Glucocorticoids promote TGFβ signaling through the Acvrl1/Smad1/5/8 axis and blunt Tgfbr1/Smad2/3 signaling in lung fibroblasts. This shift is mediated by glucocorticoid-induced upregulation of the accessory receptor Tgfbr3 (betaglycan), which acts as a 'switch' potentiating Acvrl1/Smad1 while blunting Tgfbr1/Smad2/3 signaling. Multiple glucocorticoid treatments, primary lung fibroblasts and endothelial cells, Smad phosphorylation, siRNA for Tgfbr3, in vivo dexamethasone administration to mice The Journal of biological chemistry Medium 24347165
2022 Hepatic endothelial ALK1 signaling (via BMP9/ALK1/ID axis) regulates Wnt2 and R-spondin-3 expression in liver sinusoidal endothelial cells, maintaining metabolic liver zonation. Loss of ALK1 in hepatic endothelial cells leads to vascular malformations, loss of LSEC identity, and disruption of metabolic liver zonation. LSEC-selective Acvrl1 KO mice (Stab2-iCreF3), transcriptomics, ID1-3 function inhibition, in vitro ALK1 stimulation/inhibition in LSEC Hepatology (Baltimore, Md.) High 35776660
2012 BMP9 induces EphrinB2 expression in arterial endothelial cells through an ALK1-BMPRII/ActRII-ID1/ID3-dependent pathway. Loss of ALK1 reduces EphrinB2 expression, increases VEGFR2 expression, and enhances capillary sprouting and arteriovenous anastomosis. siRNA knockdown (ALK1, BMPRII, ActRII, ID1, ID3), BMP9 stimulation, immunostaining, in vitro angiogenesis assay Angiogenesis Medium 22622516
2019 In zebrafish, combined loss of bmp10 and bmp10-like (but not bmp9) results in embryonic lethal cranial AVMs indistinguishable from acvrl1 mutants. In juvenile-to-adult period, bmp10 (not bmp9 or bmp10-like) is the non-redundant ALK1 ligand required to maintain the post-embryonic vasculature. Zebrafish genetic mutants (bmp9, bmp10, bmp10-like single and compound), vascular phenotype analysis Angiogenesis High 31828546
2022 ALK1 is localized to Caveolin-1-positive early endosomes under atheroprone (low laminar) shear stress conditions, and this endosomal compartment constitutes a signaling hub for BMP9-ALK1-Endoglin-SMAD1 signaling. Endoglin knockdown under these conditions exacerbates SMAD1/5 phosphorylation. Confocal microscopy, subcellular fractionation, siRNA knockdown, long-term shear stress application in HUVECs BMC biology Medium 36171573
2005 Functional analysis of 11 HHT2-related ALK1 kinase domain mutations revealed two mechanisms: some mutations generate a dominant-negative effect while others result in null phenotypes via loss of protein expression or receptor activity. Site-directed mutagenesis, reporter assay in mammalian cells, zebrafish embryo injection Blood Medium 16282348

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Molecular cell 593 14580334
2004 Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction. The EMBO journal 551 15385967
2002 Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development (Cambridge, England) 310 12050147
2012 ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway. Developmental cell 302 22421041
2009 Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. Journal of immunology (Baltimore, Md. : 1950) 234 19494318
2010 Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. American journal of respiratory and critical care medicine 228 20056902
2007 ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood 184 17911384
2006 SMAD4 mutations found in unselected HHT patients. Journal of medical genetics 184 16613914
1999 Smad1 recognition and activation by the ALK1 group of transforming growth factor-beta family receptors. The Journal of biological chemistry 181 9920917
2011 Interaction between alk1 and blood flow in the development of arteriovenous malformations. Development (Cambridge, England) 170 21389051
2007 Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network. Genetics in medicine : official journal of the American College of Medical Genetics 169 17224686
2003 A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2. Human molecular genetics 148 12588795
2008 ALK1 opposes ALK5/Smad3 signaling and expression of extracellular matrix components in human chondrocytes. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 132 18333754
2016 Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells. Nature communications 128 27869117
2010 ALK1-Fc inhibits multiple mediators of angiogenesis and suppresses tumor growth. Molecular cancer therapeutics 127 20124460
1999 Assignment of transforming growth factor beta1 and beta3 and a third new ligand to the type I receptor ALK-1. The Journal of biological chemistry 125 10187774
2007 Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. Journal of thrombosis and haemostasis : JTH 122 17388964
2006 Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Human mutation 115 16752392
2014 Endothelial depletion of Acvrl1 in mice leads to arteriovenous malformations associated with reduced endoglin expression. PloS one 114 24896812
2019 Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Bi-allelic Loss of ENG or ACVRL1. American journal of human genetics 108 31630786
2000 Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2. Human molecular genetics 103 10767348
2008 L- and S-endoglin differentially modulate TGFbeta1 signaling mediated by ALK1 and ALK5 in L6E9 myoblasts. Journal of cell science 100 18303046
2004 Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Human mutation 95 15024723
2012 Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain. Arteriosclerosis, thrombosis, and vascular biology 94 23241407
2016 Alk1 controls arterial endothelial cell migration in lumenized vessels. Development (Cambridge, England) 88 27287800
2004 Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Human genetics 85 15517393
2018 ALK1 Loss Results in Vascular Hyperplasia in Mice and Humans Through PI3K Activation. Arteriosclerosis, thrombosis, and vascular biology 84 29449337
2014 Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension. PloS one 83 24956016
2017 ALK1 signaling in development and disease: new paradigms. Cellular and molecular life sciences : CMLS 81 28871312
2013 Circulating Bmp10 acts through endothelial Alk1 to mediate flow-dependent arterial quiescence. Development (Cambridge, England) 80 23863480
2017 Endoglin and alk1 as therapeutic targets for hereditary hemorrhagic telangiectasia. Expert opinion on therapeutic targets 75 28796572
2010 Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood 72 20501893
2020 Coicis semen protects against focal cerebral ischemia-reperfusion injury by inhibiting oxidative stress and promoting angiogenesis via the TGFβ/ALK1/Smad1/5 signaling pathway. Aging 71 33290255
2000 Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred. American journal of medical genetics 69 10946360
2020 Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms. Nature communications 67 32238803
2019 BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance. Angiogenesis 65 31828546
2007 Caveolin-1 interacts and cooperates with the transforming growth factor-beta type I receptor ALK1 in endothelial caveolae. Cardiovascular research 64 18065769
2011 Pulmonary hypertension in adult Alk1 heterozygous mice due to oxidative stress. Cardiovascular research 63 21859819
2014 Canonical Wnt signaling skews TGF-β signaling in chondrocytes towards signaling via ALK1 and Smad 1/5/8. Cellular signalling 61 24463008
2013 ALK1-Smad1/5 signaling pathway in fibrosis development: friend or foe? Cytokine & growth factor reviews 61 24055043
2003 Disease-associated mutations in conserved residues of ALK-1 kinase domain. European journal of human genetics : EJHG 58 12700602
2013 Glucocorticoids recruit Tgfbr3 and Smad1 to shift transforming growth factor-β signaling from the Tgfbr1/Smad2/3 axis to the Acvrl1/Smad1 axis in lung fibroblasts. The Journal of biological chemistry 57 24347165
2007 Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. Journal of human genetics 55 17786384
2022 Endothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling. Nature communications 52 35440116
2017 Quality of life in patients with hereditary haemorrhagic telangiectasia (HHT). Health and quality of life outcomes 52 28114930
2022 ALK1 signaling is required for the homeostasis of Kupffer cells and prevention of bacterial infection. The Journal of clinical investigation 50 34874921
2012 Outcomes of childhood pulmonary arterial hypertension in BMPR2 and ALK1 mutation carriers. The American journal of cardiology 50 22632830
2015 A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis. Angiogenesis 49 25557927
2006 Smad7 and protein phosphatase 1alpha are critical determinants in the duration of TGF-beta/ALK1 signaling in endothelial cells. BMC cell biology 47 16571110
2016 Regulation of the ALK1 ligands, BMP9 and BMP10. Biochemical Society transactions 46 27528761
2006 Dual function of the Drosophila Alk1/Alk2 ortholog Saxophone shapes the Bmp activity gradient in the wing imaginal disc. Development (Cambridge, England) 45 16887821
2019 Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)? Genetics in medicine : official journal of the American College of Medical Genetics 44 30760892
2012 BMP9 induces EphrinB2 expression in endothelial cells through an Alk1-BMPRII/ActRII-ID1/ID3-dependent pathway: implications for hereditary hemorrhagic telangiectasia type II. Angiogenesis 43 22622516
2020 MiR-199b-5p Suppresses Tumor Angiogenesis Mediated by Vascular Endothelial Cells in Breast Cancer by Targeting ALK1. Frontiers in genetics 42 32082362
2006 Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system. Journal of neurosurgery 41 16776339
2016 Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK)1 function. Biochemical Society transactions 37 27528762
2002 Primary brain CD30+ ALK1+ anaplastic large cell lymphoma ('ALKoma'): the first case with a combination of 'not common' variants. Annals of oncology : official journal of the European Society for Medical Oncology 37 12419758
2006 Hereditary Haemorrhagic Telangiectasia (HHT): genetic and molecular aspects. Current pharmaceutical design 36 16611099
2020 Current HHT genetic overview in Spain and its phenotypic correlation: data from RiHHTa registry. Orphanet journal of rare diseases 35 32503579
2015 Phase II evaluation of dalantercept, a soluble recombinant activin receptor-like kinase 1 (ALK1) receptor fusion protein, for the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study 0229N. Gynecologic oncology 35 25888978
2014 Novel mutations in BMPR2, ACVRL1 and KCNA5 genes and hemodynamic parameters in patients with pulmonary arterial hypertension. PloS one 35 24936649
2015 Serum induces transcription of Hey1 and Hey2 genes by Alk1 but not Notch signaling in endothelial cells. PloS one 34 25799559
2014 TGF-β & BMP receptors endoglin and ALK1: overview of their functional role and status as antiangiogenic targets. Microcirculation (New York, N.Y. : 1994) 34 25279424
2012 Structure of the Alk1 extracellular domain and characterization of its bone morphogenetic protein (BMP) binding properties. Biochemistry 33 22799562
2011 Mosaic ACVRL1 and ENG mutations in hereditary haemorrhagic telangiectasia patients. Journal of medical genetics 32 21378382
2023 Genetic or therapeutic neutralization of ALK1 reduces LDL transcytosis and atherosclerosis in mice. Nature cardiovascular research 31 39196046
2017 Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK. Oncotarget 31 28427181
2015 BMP9 Induces Cord Blood-Derived Endothelial Progenitor Cell Differentiation and Ischemic Neovascularization via ALK1. Arteriosclerosis, thrombosis, and vascular biology 31 26229139
2021 OTULIN allies with LUBAC to govern angiogenesis by editing ALK1 linear polyubiquitin. Molecular cell 29 34157307
2020 BMP-9 and LDL crosstalk regulates ALK-1 endocytosis and LDL transcytosis in endothelial cells. The Journal of biological chemistry 28 33097593
2015 The high affinity ALK1-ligand BMP9 induces a hypertrophy-like state in chondrocytes that is antagonized by TGFβ1. Osteoarthritis and cartilage 28 25681563
2015 Mononuclear cells and vascular repair in HHT. Frontiers in genetics 28 25852751
2006 DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population. Human mutation 28 16429404
2016 20-year follow-up study of Danish HHT patients-survival and causes of death. Orphanet journal of rare diseases 27 27876060
2006 Alk1 and Alk2 are two new cell cycle-regulated haspin-like proteins in budding yeast. Cell cycle (Georgetown, Tex.) 27 16855400
2022 Metformin suppresses LRG1 and TGFβ1/ALK1-induced angiogenesis and protects against ultrastructural changes in rat diabetic nephropathy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 36525822
2016 For staining of ALK protein, the novel D5F3 antibody demonstrates superior overall performance in terms of intensity and extent of staining in comparison to the currently used ALK1 antibody. Virchows Archiv : an international journal of pathology 26 27271275
2005 Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations. Human mutation 26 15712270
2022 ALK1 controls hepatic vessel formation, angiodiversity, and angiocrine functions in hereditary hemorrhagic telangiectasia of the liver. Hepatology (Baltimore, Md.) 25 35776660
2014 ALK5 and ALK1 play antagonistic roles in transforming growth factor β-induced podosome formation in aortic endothelial cells. Molecular and cellular biology 25 25266657
2005 Functional analysis of mutations in the kinase domain of the TGF-beta receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia. Blood 25 16282348
2018 Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia: experience from the Center for Osler's Disease, Uppsala University Hospital. Upsala journal of medical sciences 24 30251589
2021 Bone Marrow-Derived Alk1 Mutant Endothelial Cells and Clonally Expanded Somatic Alk1 Mutant Endothelial Cells Contribute to the Development of Brain Arteriovenous Malformations in Mice. Translational stroke research 22 34674144
2020 Genotype-Phenotype Correlations in Children with HHT. Journal of clinical medicine 22 32842615
2019 BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension. Human molecular genetics 22 30809644
2015 Context-specific interactions between Notch and ALK1 cannot explain ALK1-associated arteriovenous malformations. Cardiovascular research 22 25969392
2002 Regulation of ALK-1 signaling by the nuclear receptor LXRbeta. The Journal of biological chemistry 22 12393874
2019 A theory for polymicrogyria and brain arteriovenous malformations in HHT. Neurology 21 30584075
2016 Interaction Between ALK1 Signaling and Connexin40 in the Development of Arteriovenous Malformations. Arteriosclerosis, thrombosis, and vascular biology 20 26821948
2015 Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia. PloS one 19 26176610
2022 Atheroprone fluid shear stress-regulated ALK1-Endoglin-SMAD signaling originates from early endosomes. BMC biology 18 36171573
2021 The Dual Effect of the BMP9-ALK1 Pathway in Blood Vessels: An Opportunity for Cancer Therapy Improvement? Cancers 17 34771575
2015 Executive summary of the 11th HHT international scientific conference. Angiogenesis 17 26391603
2013 SnoN facilitates ALK1-Smad1/5 signaling during embryonic angiogenesis. The Journal of cell biology 17 24019535
2013 Increased ALK1 copy number and renal cell carcinoma-a case report. Virchows Archiv : an international journal of pathology 16 24318419
2024 Impact of heterozygous ALK1 mutations on the transcriptomic response to BMP9 and BMP10 in endothelial cells from hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension donors. Angiogenesis 15 38294582
2024 Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT. Blood 15 38457357
2023 ACVRL1 drives resistance to multitarget tyrosine kinase inhibitors in colorectal cancer by promoting USP15-mediated GPX2 stabilization. BMC medicine 15 37743483
2015 The ACVRL1 c.314-35A>G polymorphism is associated with organ vascular malformations in hereditary hemorrhagic telangiectasia patients with ENG mutations, but not in patients with ACVRL1 mutations. American journal of medical genetics. Part A 15 25847705
2018 Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in Hereditary Haemorrhagic Telangiectasia. Journal of medical genetics 14 30244195