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Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury

Published version
Peer-reviewed

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Authors

Uryga, Anna K. 
Grootaert, Mandy O. J. 
Garrido, Abel M. 
Oc, Sebnem 
Foote, Kirsty 

Abstract

Abstract: Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark of multiple vascular pathologies, including following neointimal formation after injury and atherosclerosis. However, human VSMCs in advanced atherosclerotic lesions show reduced cell proliferation, extensive and persistent DNA damage, and features of premature cell senescence. Here, we report that stress-induced premature senescence (SIPS) and stable expression of a telomeric repeat-binding factor 2 protein mutant (TRF2T188A) induce senescence of human VSMCs, associated with persistent telomeric DNA damage. VSMC senescence is associated with formation of micronuclei, activation of cGAS-STING cytoplasmic sensing, and induction of multiple pro-inflammatory cytokines. VSMC-specific TRF2T188A expression in a multicolor clonal VSMC-tracking mouse model shows no change in VSMC clonal patches after injury, but an increase in neointima formation, outward remodeling, senescence and immune/inflammatory cell infiltration or retention. We suggest that persistent telomere damage in VSMCs inducing cell senescence has a major role in driving persistent inflammation in vascular disease.

Description

Keywords

Article, /631/80/304, /631/80/509, /13/1, /13/44, /13/51, /14/19, /14/32, /38/77, /64/60, article

Journal Title

Communications Biology

Conference Name

Journal ISSN

2399-3642

Volume Title

4

Publisher

Nature Publishing Group UK