title: Resveratrol-Induced Vascular Progenitor Differentiation towards Endothelial Lineage via MiR-21/Akt/β-Catenin Is Protective in Vessel Graft Models.
abstract: OBJECTIVE
  Vessel graft failure is typically associated with arteriosclerosis, in which endothelial dysfunction/damage is a key event. Resveratrol has been shown to possess cardioprotective capacity and to reduce atherosclerosis. We aimed to study the influence of resveratrol on the behavior of resident stem cells that may contribute to graft arteriosclerosis.
  
  
  METHODS
  Vascular resident progenitor cells and embryonic stem cells were treated with resveratrol under differentiating conditions and endothelial markers expression was evaluated. Expression of miR-21 and β-catenin was also tested and exogenously modified. Effects of resveratrol treatment in an ex vivo re-endothelialization model and on mice undergone vascular graft were evaluated.
  
  
  RESULTS
  Resveratrol induced expression of endothelial markers such as CD31, VE-cadherin and eNOS in both progenitor and stem cells. We demonstrated that resveratrol significantly reduced miR-21 expression, which in turn reduced Akt phosphorylation. This signal cascade diminished the amount of nuclear β-catenin, inducing endothelial marker expression and increasing tube-like formation by progenitor cells. Both the inhibition of miR-21 and the knockdown of β-catenin were able to recapitulate the effect of resveratrol application. Ex vivo, progenitor cells treated with resveratrol produced better endothelialization of the decellularized vessel. Finally, in a mouse model of vessel graft, a resveratrol-enhanced diet was able to reduce lesion formation.
  
  
  CONCLUSIONS
  We provide the first evidence that oral administration of resveratrol can reduce neointimal formation in a model of vascular graft and elucidated the underpinning miR-21/Akt/β-catenin dependent mechanism. These findings may support the beneficial effect of resveratrol supplementation for graft failure prevention.
authors.affiliation: Cardiovascular Division, King's College London BHF Centre, London, United Kingdom.
authors.forename: Paola
authors.initials: P
authors.lastname: Campagnolo
authors.affiliation: Cardiovascular Division, King's College London BHF Centre, London, United Kingdom.
authors.forename: Xuechong
authors.initials: X
authors.lastname: Hong
authors.affiliation: Cardiovascular Division, King's College London BHF Centre, London, United Kingdom.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: di Bernardini
authors.affiliation: Cardiovascular Division, King's College London BHF Centre, London, United Kingdom.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Smyrnias
authors.affiliation: Cardiovascular Division, King's College London BHF Centre, London, United Kingdom.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Cardiovascular Division, King's College London BHF Centre, London, United Kingdom.
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D015415:Biomarkers; D001808:Blood Vessels; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D053595:Embryonic Stem Cells; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D015870:Gene Expression; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D058426:Neointima / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000077185:Resveratrol; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D019737:Transplants; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D013267:Stilbenes; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt; D000077185:Resveratrol