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Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury.
- Source :
-
Communications biology [Commun Biol] 2021 May 21; Vol. 4 (1), pp. 611. Date of Electronic Publication: 2021 May 21. - Publication Year :
- 2021
-
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 <superscript>T188A</superscript> ) 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 <superscript>T188A</superscript> 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.
- Subjects :
- Animals
Atherosclerosis etiology
Atherosclerosis metabolism
Cell Proliferation
Cells, Cultured
DNA Damage
Disease Models, Animal
Humans
Inflammation etiology
Inflammation metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microfilament Proteins physiology
Muscle Proteins physiology
Muscle, Smooth, Vascular immunology
Muscle, Smooth, Vascular metabolism
Myocytes, Smooth Muscle immunology
Myocytes, Smooth Muscle metabolism
Neointima etiology
Neointima metabolism
Telomere genetics
Telomeric Repeat Binding Protein 2 metabolism
Atherosclerosis pathology
Cellular Senescence
Inflammation pathology
Muscle, Smooth, Vascular pathology
Myocytes, Smooth Muscle pathology
Neointima pathology
Telomere pathology
Subjects
Details
- Language :
- English
- ISSN :
- 2399-3642
- Volume :
- 4
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Communications biology
- Publication Type :
- Academic Journal
- Accession number :
- 34021256
- Full Text :
- https://doi.org/10.1038/s42003-021-02123-z