ALK1 Signaling Inhibits Angiogenesis by Cooperating with the Notch Pathway
Open accessAbstract
Activin receptor-like kinase 1 (ALK1) is an endothelial-specific member of the TGF-β/BMP receptor family that is inactivated in patients with hereditary hemorrhagic telangiectasia (HHT). How ALK1 signaling regulates angiogenesis remains incompletely understood. Here we show that ALK1 inhibits angiogenesis by cooperating with the Notch pathway. Blocking Alk1 signaling during postnatal development in mice leads to retinal hypervascularization and the appearance of arteriovenous malformations (AVMs). Combined blockade of Alk1 and Notch signaling further exacerbates hypervascularization, whereas activation of Alk1 by its high-affinity ligand BMP9 rescues hypersprouting induced by Notch inhibition. Mechanistically, ALK1-dependent SMAD signaling synergizes with activated Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2, thereby repressing VEGF signaling, tip cell formation, and endothelial sprouting. Taken together, these results uncover a direct link between ALK1 and Notch signaling during vascular morphogenesis that may be relevant to the pathogenesis of HHT vascular lesions.
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TGF-β can also induce mesenchymal stem cells to differentiate into endothelial cells.
“However, TGF-β can also induce mesenchymal stem cells to differentiate into endothelial cells269.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [269]
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- Authors
- Larrivée, B., Prahst, C., Gordon, E., del Toro, R., Mathivet, T., Duarte, A., Simons, M., & Eichmann, A.
- Affiliations
- Yale University (US)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Eichmann, Anne
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 22
- Issue
- 3
- Pages
- 489-500
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC4047762
- OpenAlex
- W2014415717
- Cited by
- 359
- References
- 63
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 20 · 2023: 24 · 2022: 16 · 2021: 28 · 2020: 27 · 2019: 23 · 2018: 26 · 2017: 27 · 2016: 26 · 2015: 34 · 2014: 32 · 2013: 39 · 2012: 11
- FWCI
- 17.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 539 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Fondation pour la Recherche Médicale
- Agence Nationale de la Recherche
- Fondation Bettencourt Schueller
- Fondation Leducq
- Edward N. and Della L. Thome Memorial Foundation
- Deutsche Forschungsgemeinschaft
- Institut National de la Santé et de la Recherche Médicale
- Topics
- Health Sciences › Medicine › Genetics › Vascular Anomalies and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- ALK1, Notch signaling, angiogenesis, hereditary hemorrhagic telangiectasia, BMP9, Smad signaling, Hey1, Hey2, VEGF signaling, endothelial sprouting, arteriovenous malformation, vascular morphogenesis
- MeSH terms
- Animals, Arteriovenous Malformations, Dipeptides, Disease Models, Animal, Humans, Mice, Inbred C57BL, Repressor Proteins, Retina, Telangiectasia, Hereditary Hemorrhagic, Signal Transduction, Cell Cycle Proteins, Neovascularization, Physiologic, Activin Receptors, Type I, Activin Receptors, Type II, Vascular Endothelial Growth Factors, Mice, Smad Proteins, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Receptors, Notch, Growth Differentiation Factors, Growth Differentiation Factor 2
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