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

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 (TRF2^T188A) 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 TRF2^T188A 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.

SUBMITTER: Uryga AK

PROVIDER: S-EPMC8140103 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Uryga Anna K AK Grootaert Mandy O J MOJ Garrido Abel M AM Oc Sebnem S Foote Kirsty K Chappell Joel J Finigan Alison A Rossiello Francesca F d'Adda di Fagagna Fabrizio F Aravani Dimitra D Jorgensen Helle F HF Bennett Martin R MR

Communications biology 20210521 1

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 (TRF2<sup>T188 ...[more]

PMID: 34021256

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Project description:Graphical abstract Our data suggest that metformin regulates the level of autophagosome-lysosome fusion leading to the upregulation of autophagic flux and significantly alleviates functional and structural changes associated with aging arteries, such as collagen accumulation and elastin damage. Metformin treatment also prevents a senescence-associated secretory phenotype (SASP) and improves the proliferation and migration of senescent VSMCs. Furthermore, disrupting the autophagosome-lysosome fusion abrogates the anti-senescence effects induced by metformin in VSMCs. Autophagy process is complex and involves multiple steps, it is unknown whether p62 mediated-selected autophagy seen in metformin treatment also contributes to activation of autophagic flux. Altogether, metformin, as an anti-aging drug, together with its novel role, as a regulator of autophagic flux, contributes to reduced senescence and SASP of VSMCs. Highlights • Metformin treatment improved functional and structural changes occur in aging arteries.• Metformin treatment prevented a senescence-associated secretory phenotype and improved the proliferation and migration of senescent VSMCs.• Reduced autophagic flux during cellular and vascular senescence was reversed by metformin.• Metformin enhances autophagy flux at the level of autophagosome-lysosome fusion via upregulating LAMP1. Introduction Vascular smooth muscle cell (VSMC) senescence in the vasculature results in vascular aging as well as age-related diseases, while metformin improves the inflamm-aging profile by enhancing autophagy. However, metformin’s impact on VSMC senescence is largely undefined. Objectives To test the hypothesis that metformin exerts an anti-senescence role by restoring autophagic activity in VSMCs and vascular tissues. Methods Animal models established by angiotensin II (Ang II) induction and physiological aging and senescent primary VSMCs from the aortas of elderly patients were treated with metformin. Cellular and vascular senescence were assessed by measuring the amounts of senescence-associated β-galactosidase and senescence markers, including p21 and p53. Autophagy levels were assessed by autophagy-related protein expression, transmission electron microscope, and autolysosome staining. In order to explore the underlying mechanism of the anti-senescence effects of metformin, 4D label-free quantitative proteomics and bioinformatic analyses were conducted, with subsequent experiments validating these findings. Results Ang II-dependent senescence was suppressed by metformin in VSMCs and vascular tissues. Metformin also significantly improved arterial stiffness and alleviated structural changes in aged arteries, reduced senescence-associated secretory phenotype (SASP), and improved proliferation and migration of senescent VSMCs. Mechanistically, the proteomic analysis indicated that autophagy might contribute to metformin’s anti-senescence effects. Reduced autophagic flux was observed in Ang II-induced cellular and vascular senescence; this reduction was reversed by metformin. Specifically, metformin enhanced the autophagic flux at the autophagosome-lysosome fusion level, whereas blockade of autophagosome-lysosome fusion inhibited the anti-senescence effects of metformin. Conclusions Metformin prevents VSMC and vascular senescence by promoting autolysosome formation.

Project description:Persistently unrepaired DNA damage has been identified as a causative factor for vascular ageing. We have previously shown that a defect in the function or expression of the DNA repair endonuclease ERCC1 (excision repair cross complement 1) in mice leads to accelerated, nonatherosclerotic ageing of the vascular system from as early as 8 weeks after birth. Removal of ERCC1 from endothelial alone partly explains this ageing, as shown in endothelial-specific Ercc1 knockout mice. In this study, we determined vascular ageing due to DNA damage in vascular smooth muscle cells, as achieved by smooth muscle-selective genetic removal of ERCC1 DNA repair in mice (SMC-KO: SM22αCre+ Ercc1fl/-). Vascular ageing features in SMC-KO and their wild-type littermates (WT: SM22αCre+ Ercc1fl/+) were examined at the age of 14 weeks and 25 weeks. Both SMC-KO and WT mice were normotensive. Compared to WT, SMC-KO showed a reduced heart rate, fractional shortening, and cardiac output. SMC-KO showed progressive features of nonatherosclerotic vascular ageing as they aged from 14 to 25 weeks. Decreased subcutaneous microvascular dilatation and increased carotid artery stiffness were observed. Vasodilator responses measured in aortic rings in organ baths showed decreased endothelium-dependent and endothelium-independent responses, mostly due to decreased NO-cGMP signaling. NADPH oxidase 2 and phosphodiesterase 1 inhibition improved dilations. SMC-KO mice showed elevated levels of various cytokines that indicate a balance shift in pro- and anti-inflammatory pathways. In conclusion, SMC-KO mice showed a progressive vascular ageing phenotype in resistant and conduit arteries that is associated with cardiac remodeling and contractile dysfunction. The changes induced by DNA damage might be limited to VSMC but eventually affect EC-mediated responses. The fact that NADPH oxidase 2 as wells as phosphodiesterase 1 inhibition restores vasodilation suggests that both decreased NO bioavailability and cGMP degradation play a role in local vascular smooth muscle cell ageing induced by DNA damage.

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

Publications

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

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