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

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Anna K. Uryga ◽  
Mandy O. J. Grootaert ◽  
Abel M. Garrido ◽  
Sebnem Oc ◽  
Kirsty Foote ◽  
...  
Keyword(s):  
Dna Damage ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Immune Cell ◽  
Cell Senescence ◽  
Telomeric Dna ◽  
Neointimal Formation ◽  
Persistent Inflammation ◽  
Vessel Injury ◽  
Stress Induced Premature Senescence

AbstractAccumulation 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.

scholarly journals S100B is required for maintaining an intermediate state with double-positive Sca-1+ progenitor and vascular smooth muscle cells during neointimal formation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yan Wu ◽  
Xin Liu ◽  
Ling-Yun Guo ◽  
Lei Zhang ◽  
Fei Zheng ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Progenitor Cells ◽  
Vascular Smooth Muscle Cells ◽  
Intermediate State ◽  
Muscle Cells ◽  
Neointimal Formation ◽  
Double Positive ◽  
Vessel Injury

Abstract Introduction Accumulation of vascular smooth muscle cells (VSMCs) within the neointimal region is a hallmark of atherosclerosis and vessel injury. Evidence has shown that Sca-1-positive (Sca-1+) progenitor cells residing in the vascular adventitia play a crucial role in VSMC assemblages and intimal lesions. However, the underlying mechanisms, especially in the circumstances of vascular injury, remain unknown. Methods and results The neointimal formation model in rats was established by carotid artery balloon injury using a 2F-Forgaty catheter. Most Sca-1+ cells first appeared at the adventitia of the vascular wall. S100B expressions were highest within the adventitia on the first day after vessel injury. Along with the sequentially increasing trend of S100B expression in the intima, media, and adventitia, respectively, the numbers of Sca-1+ cells were prominently increased at the media or neointima during the time course of neointimal formation. Furthermore, the Sca-1+ cells were markedly increased in the tunica media on the third day of vessel injury, SDF-1α expressions were obviously increased, and SDF-1α levels and Sca-1+ cells were almost synchronously increased within the neointima on the seventh day of vessel injury. These effects could effectually be reversed by knockdown of S100B by shRNA, RAGE inhibitor (SPF-ZM1), or CXCR4 blocker (AMD3100), indicating that migration of Sca-1+ cells from the adventitia into the neointima was associated with S100B/RAGE and SDF-1α/CXCR4. More importantly, the intermediate state of double-positive Sca-1+ and α-SMA cells was first found in the neointima of injured arteries, which could be substantially abrogated by using shRNA for S100B or blockade of CXCR4. S100B dose-dependently regulated SDF-1α expressions in VSMCs by activating PI3K/AKT and NF-κB, which were markedly abolished by PI3K/AKT inhibitor wortmannin and enhanced by p65 blocker PDTC. Furthermore, S100B was involved in human umbilical cord-derived Sca-1+ progenitor cells’ differentiation into VSMCs, especially in maintaining the intermediate state of double-positive Sca-1+ and α-SMA. Conclusions S100B triggered neointimal formation in rat injured arteries by maintaining the intermediate state of double-positive Sca-1+ progenitor and VSMCs, which were associated with direct activation of RAGE by S100B and indirect induction of SDF-1α by activating PI3K/AKT and NF-κB.

scholarly journals Curcumin inhibits proliferation, migration and neointimal formation of vascular smooth muscle via activating miR-22

2020 ◽  
Vol 58 (1) ◽  
pp. 610-619
Author(s):  
Minghua Zhang ◽  
Yuntian Li ◽  
Hui Xie ◽  
Jing Chen ◽  
Shiming Liu
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Neointimal Formation

Sirtuin 1 deficiency promotes DNA damage in vascular smooth muscle cells and aggravates atherosclerosis

2012 ◽  
Vol 56 (5-6) ◽  
pp. 313
Author(s):  
Sheetal Kumar ◽  
Haixiang Yu ◽  
Nichola Figg ◽  
John Mercer ◽  
Martin R. Bennett ◽  
...  
Keyword(s):  
Dna Damage ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Sirtuin 1

Abstract 315: Krüppel-like Factor 5 Promotes Vascular Remodeling in a Biphasic Manner by Inhibiting Vascular Smooth Muscle Cell Apoptosis and Stimulating Cell Growth

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Daigo Sawaki ◽  
Toru Suzuki ◽  
Kenichi Aizawa ◽  
Takayoshi Matsumura ◽  
Nanae Kada ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Cell Growth ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Cyclin D1 ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Vascular Remodeling ◽  
Neointimal Formation

Introduction: Vascular remodeling is characterized by cell proliferation and/or apoptosis with further phenotypic change of vascular cells. Vascular smooth muscle cell (VSMC)s, in particular, play a major role in the proliferative process such as neointimal formation and restenosis after angioplasty. In deciphering the transcriptional regulatory mechanisms in cardiovascular remodeling, Krüppel-like factor 5 (KLF5) was originally isolated as a regulatory factor of phenotypically modulated VSMCs. Past studies collectively have shown that KLF5 can induce cell growth pathologically in non-cardiovascular cells. However, how KLF5 contributes to vascular remodeling, notably its effects on apoptosis in the vascular lesion, had yet to be addressed. In the present study, we have aimed to address the effects of KLF5 not only on VSMC growth but also on apoptosis in vascular remodeling. Methods&Results: We performed adenoviral overexpression of KLF5 and other related factors after rat carotid balloon injury. In the early phase (48 hours after injury), KLF5 administered animals showed significantly decreased TUNEL positive cells in the medial layer. In the chronic phase (14 days after injury), apoptotic cells were recognized neither in the KLF5 animals nor in the others. While, neointimal formation and PCNA labeling index significantly increased in the KLF5 animals. Rat VSMCs transfected with KLF5 showed marked increase in cell proliferation and BrdU uptake. Additionally, cleavage of caspase-3 recognized in the quiescent VSMCs was attenuated after transfection of KLF5. Even under apoptotic stimulation using anisomysin, KLF5 overexpression resulted in significant inhibition of apoptosis induction. Further, KLF5 up-regulated gene expression of cell cycle factors such as cyclin D1, and conversely, knockdown of KLF5 by RNA interference showed down-regulation of cyclin D1 and impairment of VSMC proliferation. Conclusion: These findings taken together suggest that KLF5 plays a central role in VSMC proliferative pathologies such as vascular remodeling through biphasic contribution; inhibition of apoptosis and growth stimulation. Therapeutic intervention targeted against KLF5 may be potentially exploitable for VSMC proliferative pathology.

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