ArticleThe Journal of clinical investigation2014
RASA1 functions in EPHB4 signaling pathway to suppress endothelial mTORC1 activity.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
38 citing papers in PubMed, 89 citations in OpenAlex.
- From Somatic Driver to Molecular Therapy in Retinal, Choroidal and Periocular Vascular Disease: Mosaicism, Targetable Pathways and Ocular Toxicity.International journal of molecular sciences · 2026Review
- Capillary Malformation-Arteriovenous Malformation Syndrome Associated with RASA1 and EPHB4 Mutations: Comparative Case Series and Narrative Review.Life (Basel, Switzerland) · 2026Review
- Chinese capillary malformation-arteriovenous malformation: clinical and genetic analysis of eight cases.Frontiers in medicine · 2026Article
- Reversal of cerebrovascular anomalies in a zebrafish model of vein of Galen aneurysm.Nature cardiovascular research · 2025Article
- Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition.Angiogenesis · 2024Article
- Recent advances of the Ephrin and Eph family in cardiovascular development and pathologies.iScience · 2024Review
- Review
- Discovery and Characterization of Ephrin B2 and EphB4 Dysregulation and Novel Mutations in Cerebral Cavernous Malformations: In Vitro and Patient-Derived Evidence of Ephrin-Mediated Endothelial Cell Pathophysiology.Cellular and molecular neurobiology · 2023Article
- Understanding the pathogenesis of brain arteriovenous malformation: genetic variations, epigenetics, signaling pathways, and immune inflammation.Human genetics · 2023Review
- Transluminal Pillars-Their Origin and Role in the Remodelling of the Zebrafish Caudal Vein Plexus.International journal of molecular sciences · 2023Article
- Shaping the brain vasculature in development and disease in the single-cell era.Nature reviews. Neuroscience · 2023Review
- GTP-Binding Protein 1-Like (GTPBP1l) Regulates Vascular Patterning during Zebrafish Development.Biomedicines · 2022Article
- Molecular Mechanisms Driving Lymphedema and Other Lymphatic Anomalies.Cold Spring Harbor perspectives in medicine · 2022Article
- Small GTPases and Their Regulators: A Leading Road toward Blood Vessel Development in Zebrafish.International journal of molecular sciences · 2022Review
- Angiogenesis depends upon EPHB4-mediated export of collagen IV from vascular endothelial cells.JCI insight · 2022Article
- The RASopathies: from pathogenetics to therapeutics.Disease models & mechanisms · 2022Review
- Arteriovenous Cerebral High Flow Shunts in Children: From Genotype to Phenotype.Frontiers in pediatrics · 2022Article
- Review of treatment and therapeutic targets in brain arteriovenous malformation.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2021Review
- Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation.Molecular genetics & genomic medicine · 2021Article
- Zebrafish Vascular Development: General and Tissue-Specific Regulation.Journal of lipid and atherosclerosis · 2021Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Vascular malformations are linked to mutations in RAS p21 protein activator 1 (RASA1, also known as p120RasGAP); however, due to the global expression of this gene, it is unclear how these mutations specifically affect the vasculature. Here, we tested the hypothesis that RASA1 performs a critical effector function downstream of the endothelial receptor EPHB4. In zebrafish models, we found that either RASA1 or EPHB4 deficiency induced strikingly similar abnormalities in blood vessel formation and function. Expression of WT EPHB4 receptor or engineered receptors with altered RASA1 binding revealed that the ability of EPHB4 to recruit RASA1 is required to restore blood flow in EPHB4-deficient animals. Analysis of EPHB4-deficient zebrafish tissue lysates revealed that mTORC1 is robustly overactivated, and pharmacological inhibition of mTORC1 in these animals rescued both vessel structure and function. Furthermore, overexpression of mTORC1 in endothelial cells exacerbated vascular phenotypes in animals with reduced EPHB4 or RASA1, suggesting a functional EPHB4/RASA1/mTORC1 signaling axis in endothelial cells. Tissue samples from patients with arteriovenous malformations displayed strong endothelial phospho-S6 staining, indicating increased mTORC1 activity. These results indicate that deregulation of EPHB4/RASA1/mTORC1 signaling in endothelial cells promotes vascular malformation and suggest that mTORC1 inhibitors, many of which are approved for the treatment of certain cancers, should be further explored as a potential strategy to treat patients with vascular malformations.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.