@article{Warboys:2014:10.1161/ATVBAHA.114.303415,
author = {Warboys, CM and de, Luca A and Amini, N and Luong, L and Duckles, H and Hsiao, S and White, A and Biswas, S and Khamis, R and Chong, CK and Cheung, W-M and Sherwin, SJ and Bennett, MR and Gil, J and Mason, JC and Haskard, DO and Evans, PC},
doi = {10.1161/ATVBAHA.114.303415},
journal = {Arteriosclerosis, Thrombosis and Vascular Biology},
pages = {985--995},
title = {Disturbed flow promotes endothelial senescence via a p53-dependent Ppathway},
url = {http://dx.doi.org/10.1161/ATVBAHA.114.303415},
volume = {34},
year = {2014}
}

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TY  - JOUR
AB  - 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&ndas
AU  - Warboys,CM
AU  - de,Luca A
AU  - Amini,N
AU  - Luong,L
AU  - Duckles,H
AU  - Hsiao,S
AU  - White,A
AU  - Biswas,S
AU  - Khamis,R
AU  - Chong,CK
AU  - Cheung,W-M
AU  - Sherwin,SJ
AU  - Bennett,MR
AU  - Gil,J
AU  - Mason,JC
AU  - Haskard,DO
AU  - Evans,PC
DO  - 10.1161/ATVBAHA.114.303415
EP  - 995
PY  - 2014///
SN  - 1079-5642
SP  - 985
TI  - Disturbed flow promotes endothelial senescence via a p53-dependent Ppathway
T2  - Arteriosclerosis, Thrombosis and Vascular Biology
UR  - http://dx.doi.org/10.1161/ATVBAHA.114.303415
UR  - https://www.ahajournals.org/doi/10.1161/ATVBAHA.114.303415
VL  - 34
ER  - 

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