Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model
Open Access
- 25 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 12 (1), 1-22
- https://doi.org/10.1038/s41467-020-20774-0
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.Funding Information
- American Heart Association (19CDA34760284)
- National institute of Health, NHBLI, USA
This publication has 76 references indexed in Scilit:
- Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivoNature Communications, 2012
- Developmental timing of CCM2 loss influences cerebral cavernous malformations in miceThe Journal of Experimental Medicine, 2011
- Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036Cancer Cell, 2011
- Conversion of vascular endothelial cells into multipotent stem-like cellsNature Medicine, 2010
- A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human diseaseHuman Molecular Genetics, 2010
- A PP2A Phosphatase High Density Interaction Network Identifies a Novel Striatin-interacting Phosphatase and Kinase Complex Linked to the Cerebral Cavernous Malformation 3 (CCM3) ProteinMolecular & Cellular Proteomics, 2009
- Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesisHuman Molecular Genetics, 2008
- A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cellsHuman Molecular Genetics, 2008
- Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformationsNature Genetics, 2008
- Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cellsProceedings of the National Academy of Sciences of the United States of America, 2006