title: Cyclooxygenase-2-derived prostaglandin E₂ promotes injury-induced vascular neointimal hyperplasia through the E-prostanoid 3 receptor.
abstract: BACKGROUND
  Vascular smooth muscle cell (VSMC) migration and proliferation are the hallmarks of restenosis pathogenesis after angioplasty. Cyclooxygenase (COX)-derived prostaglandin (PG) E₂ is implicated in the vascular remodeling response to injury. However, its precise molecular role remains unknown.
  
  
  OBJECTIVE
  This study investigates the impact of COX-2-derived PGE₂ on neointima formation after injury.
  
  
  RESULTS
  Vascular remodeling was induced by wire injury in femoral arteries of mice. Both neointima formation and the restenosis ratio were diminished in COX-2 knockout mice as compared with controls, whereas these parameters were enhanced in COX-1>COX-2 mice, in which COX-1 is governed by COX-2 regulatory elements. PG profile analysis revealed that the reduced PGE₂ by COX-2 deficiency, but not PGI2, could be rescued by COX-1 replacement, indicating COX-2-derived PGE₂ enhanced neointima formation. Through multiple approaches, the EP3 receptor was identified to mediate the VSMC migration response to various stimuli. Disruption of EP3 impaired VSMC polarity for directional migration by decreasing small GTPase activity and restricted vascular neointimal hyperplasia, whereas overexpression of EP3α and EP3β aggravated neointima formation. Inhibition or deletion of EP3α/β, a Gαi protein-coupled receptor, activated the cAMP/protein kinase A pathway and decreased activation of RhoA in VSMCs. PGE₂ could stimulate phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase3β signaling in VSMCs through Gβγ subunits on EP3α/β activation. Ablation of EP3 suppressed phosphatidylinositol 3-kinase signaling and reduced GTPase activity in VSMCs and altered cell polarity and directional migration.
  
  
  CONCLUSIONS
  COX-2-derived PGE₂ facilitated the neointimal hyperplasia response to injury through EP3α/β-mediated cAMP/protein kinase A and phosphatidylinositol 3-kinase pathways, indicating EP3 inhibition may be a promising therapeutic strategy for percutaneous transluminal coronary angioplasty.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zou
authors.forename: Juan
authors.initials: J
authors.lastname: Tang
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Gong
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Wang
authors.forename: Yujun
authors.initials: Y
authors.lastname: Shen
authors.forename: Lixia
authors.initials: L
authors.lastname: Xiong
authors.forename: Richard M
authors.initials: RM
authors.lastname: Breyer
authors.forename: Michael
authors.initials: M
authors.lastname: Lazarus
authors.forename: Colin D
authors.initials: CD
authors.lastname: Funk
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D005263:Femoral Artery / Q000293:injuries* / Q000378:metabolism*; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000293:injuries / Q000378:metabolism; D058426:Neointima / Q000235:genetics / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000235:genetics / Q000378:metabolism*
chemical_list: D058308:Receptors, Prostaglandin E, EP3 Subtype; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone
keywords: EP3; neointima formation; polarity; prostaglandin E2; vascular smooth muscle cell migration