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

Commun Biol. 2021 May 21;4(1):611. doi: 10.1038/s42003-021-02123-z.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / etiology
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology*
  • Cell Proliferation
  • Cells, Cultured
  • Cellular Senescence*
  • DNA Damage
  • Disease Models, Animal
  • Humans
  • Inflammation / etiology
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microfilament Proteins / physiology
  • Muscle Proteins / physiology
  • Muscle, Smooth, Vascular / immunology
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology*
  • Myocytes, Smooth Muscle / immunology
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology*
  • Neointima / etiology
  • Neointima / metabolism
  • Neointima / pathology*
  • Telomere / genetics
  • Telomere / pathology*
  • Telomeric Repeat Binding Protein 2 / metabolism


  • Microfilament Proteins
  • Muscle Proteins
  • TERF2 protein, human
  • Tagln protein, mouse
  • Telomeric Repeat Binding Protein 2