title: Disturbed flow promotes endothelial senescence via a p53-dependent pathway.
abstract: 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.
  
  
  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.
authors.affiliation: 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 Kingdom; and Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom (M.R.B.).
authors.forename: Christina M
authors.initials: CM
authors.lastname: Warboys
authors.forename: Amalia
authors.initials: A
authors.lastname: de Luca
authors.forename: Narges
authors.initials: N
authors.lastname: Amini
authors.forename: Le
authors.initials: L
authors.lastname: Luong
authors.forename: Hayley
authors.initials: H
authors.lastname: Duckles
authors.forename: Sarah
authors.initials: S
authors.lastname: Hsiao
authors.forename: Alex
authors.initials: A
authors.lastname: White
authors.forename: Shukti
authors.initials: S
authors.lastname: Biswas
authors.forename: Ramzi
authors.initials: R
authors.lastname: Khamis
authors.forename: Chuh K
authors.initials: CK
authors.lastname: Chong
authors.forename: Wai-Mun
authors.initials: WM
authors.lastname: Cheung
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Sherwin
authors.forename: Martin R
authors.initials: MR
authors.lastname: Bennett
authors.forename: Jesus
authors.initials: J
authors.lastname: Gil
authors.forename: Justin C
authors.initials: JC
authors.lastname: Mason
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
authors.forename: Paul C
authors.initials: PC
authors.lastname: Evans
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019149:Bioreactors; D002465:Cell Movement; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012039:Regional Blood Flow; D056564:Sirtuin 1 / Q000378:metabolism; D013314:Stress, Mechanical; D013552:Swine; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020536:Enzyme Activators; D011973:Receptors, LDL; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: aging; endothelium; sirtuin 1