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 (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.

circ-Sirt1 Decelerates Senescence by Inhibiting p53 Activation in Vascular Smooth Muscle Cells, Ameliorating Neointima Formation

“…This phenomenon can be attributed to the greater proliferation ability of dedifferentiated VSMCs in the neointima, as repeated cell division leads to critical shortening and erosion of the telomeres and loss of the protective shelterin complex, which results in a persistent DNA damage response (DDR) that instigates senescence (9). Contradictively, another study showed increased SA-β-gal areas in both media and neointima (40). In addition, we found increased p53 positive cells and decreased circ-Sirt1 expression within atherosclerotic lesion of ApoE −/− mice fed with Paigen diet compared with WT mice.…”

Epigenetic dysregulation in cardiovascular aging and disease

“…Angiotensin II is another well-described driver of VSMC senescence, and recently, smooth muscle 22α, an actin-binding protein, has been shown to prevent p53 degradation via MDM2 suppression to promote angiotensin II-induced VSMC senescence [75] . Importantly, senescent VSMCs in the plaque of carotid arteries express enhanced levels of interleukin-6 (IL-6), signifying VSMCs as a SASP producer and source of inflammation during vascular disease [76] . Most recently, Uryga et al [77] suggested persistent telomere damage in VSMCs causes senescence and inflammation via immune cell recruitment and retention.…”

“…Most recently, Uryga et al . [ 77 ] suggested persistent telomere damage in VSMCs causes senescence and inflammation via immune cell recruitment and retention. Overall, senescent VSMCs have been recognized in atherosclerotic lesions, AAA, and PAD, suggesting that VSMCs have a critical role in age-related vascular pathologies [ 70 ] .…”

Mechanisms of vascular smooth muscle cell investment and phenotypic diversification in vascular diseases

“…Using multicolour lineage tracing systems, where cells stochastically express one of multiple differently coloured reporter proteins that are inherited by progeny, it was shown that the extensive VSMC contribution to vascular remodelling arises from the clonal expansion of few pre-existing cells in atherosclerosis [ 7 , 8 , 10 , 23 , 26 ], acute vascular injury [ 7 , 27 ], aneurysm [ 14 , 15 ] and PAH [ 16 , 17 ]. The observation of VSMC clonal expansion in multiple diseases suggests that selective cell expansion is a programmed feature of adult VSMCs, in contrast with the widespread proliferation and extensive mixing of VSMC clones during embryonic development [ 10 , 28 ].…”