ArticleNature medicine2016
Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation.
Article in Nature medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 90 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
90 citing papers in PubMed, 1 synthesis or guideline pooled it, 140 citations in OpenAlex.
- Rho-associated kinase inhibitors in cerebral cavernous malformations: a preclinical systematic review.Neurosurgical review · 2026Pooled it
- Cerebral cavernous malformations: epidemiology, molecular pathogenesis, diagnosis and therapy.Molecular biomedicine · 2026Review
- Inhibition of MEKK3 Prevents Cerebral Cavernous Malformation Progression Via Restoring Endothelial Integrity and Restricting Microglial Activation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Relationship between CCM3 expression and angiogenesis in esophageal squamous cell carcinoma and its possible mechanism.International journal of clinical oncology · 2026Article
- A targeted vector for brain endothelial cell gene delivery and cerebrovascular malformation modelling.Nature biomedical engineering · 2026Article
- Article
- TIE2 links MEKK3-KLF2/4 and PI3K signaling in cerebral cavernous malformation.The Journal of experimental medicine · 2026Article
- MEKK3 bridges gut-brain communication and cerebral cavernous malformation pathogenesis.Cell death discovery · 2026Review
- Identification of diagnostic and prognostic phospholipid biomarkers in idiopathic pulmonary fibrosis via machine learning and in vivo validation.Human genomics · 2025Article
- MAPK signaling and angiopoietin-2 contribute to endothelial permeability in capillary malformations.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Common and distinct circulating microRNAs in four neurovascular disorders.Biochemistry and biophysics reports · 2025Article
- mTORC1 Signaling in Brain Endothelial Progenitors Contributes to CCM Pathogenesis.Circulation research · 2024Article
- GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas.American journal of human genetics · 2024Article
- A renaissance of cerebral cavernous malformation proteins in vascular physiology.Nature cardiovascular research · 2024Article
- Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids.Cell stem cell · 2024Article
- Shear stress and pathophysiological PI3K involvement in vascular malformations.The Journal of clinical investigation · 2024Review
- CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation.Circulation research · 2024Article
- Evolution of chromosome-arm aberrations in breast cancer through genetic network rewiring.Cell reports · 2024Article
- Capillary malformations.The Journal of clinical investigation · 2024Review
- Circulating biomarkers in familial cerebral cavernous malformation.EBioMedicine · 2024Article
30 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
16 authors at 4 institutions in 2 countries.
Funding
Abstract
Cerebral cavernous malformations (CCMs) are vascular malformations that affect the central nervous system and result in cerebral hemorrhage, seizure and stroke. CCMs arise from loss-of-function mutations in one of three genes: KRIT1 (also known as CCM1), CCM2 or PDCD10 (also known as CCM3). PDCD10 mutations in humans often result in a more severe form of the disease relative to mutations in the other two CCM genes, and PDCD10-knockout mice show severe defects, the mechanistic basis for which is unclear. We have recently reported that CCM3 regulates exocytosis mediated by the UNC13 family of exocytic regulatory proteins. Here, in investigating the role of endothelial cell exocytosis in CCM disease progression, we found that CCM3 suppresses UNC13B- and vesicle-associated membrane protein 3 (VAMP3)-dependent exocytosis of angiopoietin 2 (ANGPT2) in brain endothelial cells. CCM3 deficiency in endothelial cells augments the exocytosis and secretion of ANGPT2, which is associated with destabilized endothelial cell junctions, enlarged lumen formation and endothelial cell-pericyte dissociation. UNC13B deficiency, which blunts ANGPT2 secretion from endothelial cells, or treatment with an ANGPT2-neutralizing antibody normalizes the defects in the brain and retina caused by endothelial-cell-specific CCM3 deficiency, including the disruption of endothelial cell junctions, vessel dilation and pericyte dissociation. Thus, enhanced secretion of ANGPT2 in endothelial cells contributes to the progression of CCM disease, providing a new therapeutic approach for treating this devastating pathology.
Indexed as
Identifiers
What OpenQuestion holds
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.