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Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model
- Source :
- Nature Communications, Nature Communications, Vol 12, Iss 1, Pp 1-22 (2021)
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
Abstract
- Cerebral cavernous malformations (CCMs) are vascular abnormalities that primarily occur in adulthood and cause cerebral hemorrhage, stroke, and seizures. CCMs are thought to be initiated by endothelial cell (EC) loss of any one of the three Ccm genes: CCM1 (KRIT1), CCM2 (OSM), or CCM3 (PDCD10). Here we report that mice with a brain EC-specific deletion of Pdcd10 (Pdcd10BECKO) survive up to 6-12 months and develop bona fide CCM lesions in all regions of brain, allowing us to visualize the vascular dynamics of CCM lesions using transcranial two-photon microscopy. This approach reveals that CCMs initiate from protrusion at the level of capillary and post-capillary venules with gradual dissociation of pericytes. Microvascular beds in lesions are hyper-permeable, and these disorganized structures present endomucin-positive ECs and α-smooth muscle actin-positive pericytes. Caveolae in the endothelium of Pdcd10BECKO lesions are drastically increased, enhancing Tie2 signaling in Ccm3-deficient ECs. Moreover, genetic deletion of caveolin-1 or pharmacological blockade of Tie2 signaling effectively normalizes microvascular structure and barrier function with attenuated EC-pericyte disassociation and CCM lesion formation in Pdcd10BECKO mice. Our study establishes a chronic CCM model and uncovers a mechanism by which CCM3 mutation-induced caveolae-Tie2 signaling contributes to CCM pathogenesis.<br />Animal models that fully recapitulate human CCM pathogenesis are not currently available. Here, the authors establish a novel CCM model and reveal that caveolae-Tie2 signaling is involved in CCMs formation at the level of venules, which is accompanied by gradual dissociation of pericytes.
- Subjects :
- 0301 basic medicine
Hemangioma, Cavernous, Central Nervous System
Endothelium
Science
General Physics and Astronomy
Mice, Transgenic
Caveolae
Article
General Biochemistry, Genetics and Molecular Biology
Pathogenesis
03 medical and health sciences
0302 clinical medicine
Microscopy, Electron, Transmission
medicine
Animals
Humans
Vascular diseases
Stroke
Cells, Cultured
Barrier function
Mice, Knockout
Multidisciplinary
biology
business.industry
Brain
Endothelial Cells
General Chemistry
medicine.disease
Receptor, TIE-2
Survival Analysis
Angiopoietin receptor
Blockade
Cell biology
Endothelial stem cell
Disease Models, Animal
Mechanisms of disease
030104 developmental biology
medicine.anatomical_structure
biology.protein
Apoptosis Regulatory Proteins
Pericytes
business
030217 neurology & neurosurgery
Cell signalling
Signal Transduction
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....dcc2e6b33eacfb209bf84ec5caf7d24a
- Full Text :
- https://doi.org/10.1038/s41467-020-20774-0