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

A Uryga,M.O.J Grootaert,A Garrido,S Oc,K Foote,J Chappell,A Finigan,F Rossiello,F D'Adda Di Fagagna,D Aravani,H.F Jorgensen,M Bennett

doi:10.1016/j.atherosclerosis.2021.06.076

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

A Uryga, M.O.J Grootaert + Show 10 more

Open Access

https://doi.org/10.1016/j.atherosclerosis.2021.06.076

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Journal: Atherosclerosis	Publication Date: Aug 1, 2021
Citations: 1	License type: cc-by

Affiliation: University of Cambridge

Abstract

Background and Aims: Vascular smooth muscle cells (VSMCs) accumulate in injury-induced neointimal lesions and atherosclerotic plaques in an oligoclonal fashion, yet plaque VSMCs show reduced proliferation and cell senescence. DNA damage leads to VSMC senescence and inflammation and VSMC senescence promotes atherosclerosis; however, the exact mechanism by which VSMC senescence promotes lesion formation is not known. Here, we investigated telomere damage-induced VSMC senescence, the contribution of senescence-induced inflammation and the mechanisms involved, the consequences of VSMC senescence in vivo after injury, and whether it promotes clonality.

Highlights

Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark of multiple vascular pathologies, including following neointimal formation after injury and atherosclerosis
Telomeric repeat-binding factor 2 (TRF2) is a key shelterin protein responsible for telomere protection, as conditional deletion or overexpression of mutated forms results in dysfunctional telomeres, telomere fusions, and cell senescence[6,8,28]. We show that both stress-induced premature senescence (SIPS) and expression of a mutant telomeric repeat-binding factor 2 (TRF2) protein (TRF2T188A) induce persistent telomere damage and senescence in VSMCs, and a pro-inflammatory phenotype, which is reliant on cGAS-STING signaling but restricted to a subset of pro-inflammatory genes
To study the consequences of either acute genomic DNA damage or SIPS, respectively, we harvested human VSMCs after treatment with the chemotherapeutic agent doxorubicin for 24 h, or for 1 day followed by 21 days recovery together with respective untreated controls (Fig. 1a)

Summary

Introduction

Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark of multiple vascular pathologies, including following neointimal formation after injury and atherosclerosis. Telomeric repeat-binding factor 2 (TRF2) is a key shelterin protein responsible for telomere protection, as conditional deletion or overexpression of mutated forms results in dysfunctional telomeres, telomere fusions, and cell senescence[6,8,28] We show that both SIPS and expression of a mutant TRF2 protein (TRF2T188A) induce persistent telomere damage and senescence in VSMCs, and a pro-inflammatory phenotype, which is reliant on cGAS-STING signaling but restricted to a subset of pro-inflammatory genes. Persistent telomere damage in VSMCs in vivo induces a marked pro-inflammatory/immune cell infiltrate with increased neointimal formation and vessel remodeling, but no change in clonality of VSMCs. Our results indicate that VSMC senescence may exert its major effects through inflammation rather than impaired proliferation, and persistent telomere damage may be an important driver of the chronic inflammation seen in vascular disease

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