CCM2-deficient endothelial cells undergo a ROCK-dependent reprogramming into senescence-associated secretory phenotype.
Cerebral cavernous malformations
Mechanotransduction
Microenvironment remodeling
ROCK
Senescence associated secretory phenotype
Journal
Angiogenesis
ISSN: 1573-7209
Titre abrégé: Angiogenesis
Pays: Germany
ID NLM: 9814575
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
18
03
2021
accepted:
22
07
2021
pubmed:
4
8
2021
medline:
12
2
2022
entrez:
3
8
2021
Statut:
ppublish
Résumé
Cerebral cavernous malformation (CCM) is a cerebrovascular disease in which stacks of dilated haemorrhagic capillaries form focally in the brain. Whether and how defective mechanotransduction, cellular mosaicism and inflammation interplay to sustain the progression of CCM disease is unknown. Here, we reveal that CCM1- and CCM2-silenced endothelial cells expanded in vitro enter into senescence-associated secretory phenotype (SASP) that they use to invade the extracellular matrix and attract surrounding wild-type endothelial and immune cells. Further, we demonstrate that this SASP is driven by the cytoskeletal, molecular and transcriptomic disorders provoked by ROCK dysfunctions. By this, we propose that CCM2 and ROCK could be parts of a scaffold controlling senescence, bringing new insights into the emerging field of the control of ageing by cellular mechanics. These in vitro findings reconcile the known dysregulated traits of CCM2-deficient endothelial cells into a unique endothelial fate. Based on these in vitro results, we propose that a SASP could link the increased ROCK-dependent cell contractility in CCM2-deficient endothelial cells with microenvironment remodelling and long-range chemo-attraction of endothelial and immune cells.
Identifiants
pubmed: 34342749
doi: 10.1007/s10456-021-09809-2
pii: 10.1007/s10456-021-09809-2
doi:
Substances chimiques
CCM2 protein, human
0
Carrier Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
843-860Subventions
Organisme : ANR
ID : ANR-17-CE13-022
Organisme : FRM
ID : DEQ20170336702
Organisme : FWO
ID : G087018N
Organisme : FP7 Nanosciences, Nanotechnologies, Materials and new Production Technologies
ID : FP7/2007-2013
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature B.V.
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