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Updated: Apr 19, 2026
Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice
Published on: February 20, 2019
Effects of DNA damage in smooth muscle cells in atherosclerosis
Kelly Gray1, Sheetal Kumar1, Nichola Figg1
1From the Division of Cardiovascular Medicine (K.G., S.K., N.F., J.H., L.B., J.M., M.B.) and Department of Biochemistry (T.L.), Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
Rationale:
DNA damage and the DNA damage response have been identified in human atherosclerosis, including in vascular smooth muscle cells (VSMCs). However, although double-stranded breaks (DSBs) are hypothesized to promote plaque progression and instability, in part, by promoting cell senescence, apoptosis, and inflammation, the direct effects of DSBs in VSMCs seen in atherogenesis are unknown.
Objective:
To determine the presence and effect of endogenous levels of DSBs in VSMCs on atherosclerosis.
Methods And Results:
Human atherosclerotic plaque VSMCs showed increased expression of multiple DNA damage response proteins in vitro and in vivo, particularly the MRE11/RAD50/NBS1 complex that senses DSB repair. Oxidative stress-induced DSBs were increased in plaque VSMCs, but DSB repair was maintained. To determine the effect of DSBs on atherosclerosis, we generated 2 novel transgenic mice lines expressing NBS1 or C-terminal deleted NBS1 only in VSMCs, and crossed them with apolipoprotein E(-/-) mice. SM22α-NBS1/apolipoprotein E(-/-) VSMCs showed enhanced DSB repair and decreased growth arrest and apoptosis, whereas SM22α-(ΔC)NBS1/apolipoprotein E(-/-) VSMCs showed reduced DSB repair and increased growth arrest and apoptosis. Accelerating or retarding DSB repair did not affect atherosclerosis extent or composition. However, VSMC DNA damage reduced relative fibrous cap areas, whereas accelerating DSB repair increased cap area and VSMC content.
Conclusions:
Human atherosclerotic plaque VSMCs show increased DNA damage, including DSBs and DNA damage response activation. VSMC DNA damage has minimal effects on atherogenesis, but alters plaque phenotype inhibiting fibrous cap areas in advanced lesions. Inhibiting DNA damage in atherosclerosis may be a novel target to promote plaque stability.
Insights
Vascular smooth muscle cell (VSMC) DNA damage in atherosclerosis increases, but has minimal impact on plaque development. However, it reduces fibrous cap areas, suggesting DNA damage inhibition may promote plaque stability.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Genetics
Background:
- DNA damage and the DNA damage response are present in human atherosclerosis, particularly in vascular smooth muscle cells (VSMCs).
- Double-stranded breaks (DSBs) are hypothesized to promote plaque progression and instability, but their direct effects in VSMCs are unknown.
Purpose of the Study:
- To investigate the presence and impact of endogenous double-stranded breaks (DSBs) in vascular smooth muscle cells (VSMCs) on atherosclerosis development and plaque phenotype.
Main Methods:
- Assessed DNA damage response proteins and DSBs in human atherosclerotic plaque VSMCs.
- Generated transgenic mouse models expressing NBS1 or a truncated NBS1 in VSMCs, crossed with apolipoprotein E(-/-) mice.
- Analyzed atherosclerosis extent, composition, and plaque phenotype, including fibrous cap area and VSMC content.
Main Results:
- Human atherosclerotic VSMCs exhibit increased DNA damage and activation of the DNA damage response, with maintained DSB repair.
- Modulating DSB repair in VSMCs influenced cell growth arrest and apoptosis but did not alter atherosclerosis extent or composition.
- VSMC DNA damage reduced fibrous cap areas, while accelerated DSB repair increased cap area and VSMC content.
Conclusions:
- VSMCs in human atherosclerotic plaques show elevated DNA damage and response activation.
- VSMC DNA damage minimally affects atherogenesis but significantly alters plaque phenotype by reducing fibrous cap areas.
- Targeting DNA damage in atherosclerosis could be a novel strategy to enhance plaque stability.
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