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Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model

Authors :
Lingfeng Qin
Haifeng Zhang
Qun Lin
Huanjiao Jenny Zhou
Quan Jiang
Xinran Liu
Katie N. Murray
Wang Min
Busu Li
Morven Graham
Jaime Grutzendler
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.

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