Disturbed Flow Promotes Endothelial Senescence via a p53-Dependent Pathway
Open accessAbstract
Objective—: Although atherosclerosis is associated with systemic risk factors such as age, high cholesterol, and obesity, plaque formation occurs predominately at branches and bends that are exposed to disturbed patterns of blood flow. The molecular mechanisms that link disturbed flow–generated mechanical forces with arterial injury are uncertain. To illuminate them, we investigated the effects of flow on endothelial cell (EC) senescence. Approach and Results—: LDLR −/− (low-density lipoprotein receptor −/− ) mice were exposed to a high-fat diet for 2 to 12 weeks (or to a normal chow diet as a control) before the assessment of cellular senescence in aortic ECs. En face staining revealed that senescence-associated β-galactosidase activity and p53 expression were elevated in ECs at sites of disturbed flow in response to a high-fat diet. By contrast, ECs exposed to undisturbed flow did not express senescence-associated β-galactosidase or p53. Studies of aortae from healthy pigs (aged 6 months) also revealed enhanced senescence-associated β-galactosidase staining at sites of disturbed flow. These data suggest that senescent ECs accumulate at disturbed flow sites during atherogenesis. We used in vitro flow systems to examine whether a causal relationship exists between flow and EC senescence. Exposure of cultured ECs to flow (using either an orbital shaker or a syringe-pump flow bioreactor) revealed that disturbed flow promoted EC senescence compared with static conditions, whereas undisturbed flow reduced senescence. Gene silencing studies demonstrated that disturbed flow induced EC senescence via a p53-p21 signaling pathway. Disturbed flow–induced senescent ECs exhibited reduced migration compared with nonsenescent ECs in a scratch wound closure assay, and thus may be defective for arterial repair. However, pharmacological activation of sirtuin 1 (using resveratrol or SRT1720) protected ECs from disturbed flow–induced senescence. Conclusions—: Disturbed flow promotes endothelial senescence via a p53-p21–dependent pathway which can be inhibited by activation of sirtuin 1. These observations support the principle that pharmacological activation of sirtuin 1 may promote cardiovascular health by suppressing EC senescence at atheroprone sites.
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Reduced blood flow, as occurs in obese adipose tissue, is sufficient to trigger endothelial cell senescence.
“Reduced blood flow, as seen in obese AT, is sufficient to trigger endothelial cell senescence (105, 110).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [105]
Preadipocytes, mature adipocytes, and endothelial cells can become senescent during obesity.
“Surprisingly, preadipocytes and mature adipocytes as well as endothelial cells can become senescent during obesity (105-109).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [105]
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- Authors
- Warboys, C. M., de Luca, A., Amini, N., Luong, L., Duckles, H., Hsiao, S., White, A., Biswas, S., Khamis, R., Chong, C. K., Cheung, W.-M., Sherwin, S. J., Bennett, M. R., Gil, J., Mason, J. C., Haskard, D. O., & Evans, P. C.
- Affiliations
- University of Cambridge (GB)
- From the British Heart Foundation Cardiovascular Science Unit, National Heart and Lung Institute (C.M.W., A.d.L., NA., R.K., W.-M.C., J.C.M., D.O.H.), Department of Aeronautics (S.J.S.), and MRC Clinical Sciences Centre (J.G.), Imperial College London, London, United Kingdom; Departments of Cardiovascular Science (L.L., H.D., S.H., S.B., P.C.E.) and Materials Science and Engineering (A.W., C.K.C.) and Insigneo Institute of In Silico Medicine (P.C.E.), University of Sheffield, Sheffield, United...
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2014-05
- Volume
- 34
- Issue
- 5
- Pages
- 985-995
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2099219058
- Cited by
- 227
- References
- 66
- Citations by year
- 2026: 15 · 2025: 17 · 2024: 13 · 2023: 22 · 2022: 21 · 2021: 22 · 2020: 16 · 2019: 20 · 2018: 21 · 2017: 20 · 2016: 19 · 2015: 15 · 2014: 5
- FWCI
- 13.11
- Type
- journal article
- Language
- en
- Open access
- Licence
- cc-by
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- RVC Research Online (Royal Veterinary College) (submittedVersion, cc-by)
- Funders
- British Heart Foundation (FS/10/006/27960, PG/12/16/29443, RG/13/14/30314, PG/12/82/29907)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- flow disturbance, endothelial cell senescence, p53, p21, SIRT1, resveratrol, SRT1720, atherosclerosis, atherogenesis, mechanical forces, endothelial cell migration, arterial reconstruction, high-fat diet, Ldlr knockout mice, flow bioreactor
- MeSH terms
- Animals, Aortic Diseases, Cell Movement, Cells, Cultured, Disease Models, Animal, Enzyme Activation, Humans, Mice, Inbred C57BL, Receptors, LDL, Regional Blood Flow, Stress, Mechanical, Swine, Time Factors, Transfection, Wound Healing, Tumor Suppressor Protein p53, Cellular Senescence, Mice, Knockout, Bioreactors, Enzyme Activators, RNA Interference, Mechanotransduction, Cellular, Endothelial Cells, Atherosclerosis, Cyclin-Dependent Kinase Inhibitor p21, Mice, Sirtuin 1, Diet, High-Fat, Human Umbilical Vein Endothelial Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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