title: Clopidogrel inhibits angiogenesis of gastric ulcer healing via downregulation of vascular endothelial growth factor receptor 2.
abstract: OBJECTIVE
  Although clopidogrel does not cause gastric mucosal injury, it does not prevent peptic ulcer recurrence in high-risk patients. We explored whether clopidogrel delays gastric ulcer healing via inhibiting angiogenesis and to elucidate the possible mechanisms.
  
  
  METHODS
  Gastric ulcers were induced in Sprague Dawley rats, and ulcer healing and angiogenesis of ulcer margin were compared between clopidogrel-treated rats and controls. The expressions of the proangiogenic growth factors and their receptors including basic fibroblast growth factor (bFGF), bFGF receptor (FGFR), vascular endothelial growth factor (VEGF), VEGFR1, VEGFR2, platelet-derived growth factor (PDGF)A, PDGFB, PDGFR A, PDGFR B, and phosphorylated form of mitogenic activated protein kinase pathways over the ulcer margin were compared via western blot and reverse transcription polymerase chain reaction. In vitro, human umbilical vein endothelial cells (HUVECs) were used to elucidate how clopidogrel inhibited growth factors-stimulated HUVEC proliferation.
  
  
  RESULTS
  The ulcer sizes were significantly larger and the angiogenesis of ulcer margin was significantly diminished in the clopidogrel (2 and 10 mg/kg/d) treated groups. Ulcer induction markedly increased the expression of phosphorylated form of extracellular signal-regulated kinase (pERK), FGFR2, VEGF, VEGFR2, and PDGFRA when compared with those of normal mucosa. Clopidogrel treatment significantly decreased pERK, FGFR2, VEGF, VEGFR2, and PDGFRA expression at the ulcer margin when compared with those of the respective control group. In vitro, clopidogrel (10(-6)M) inhibited VEGF-stimulated (20 ng/mL) HUVEC proliferation, at least, via downregulation of VEGFR2 and pERK.
  
  
  CONCLUSIONS
  Clopidogrel inhibits the angiogenesis of gastric ulcer healing at least partially by the inhibition of the VEGF-VEGFR2-ERK signal transduction pathway.
authors: Department of Medicine, National Yang-Ming University, School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: jcluo@vghtpe.gov.tw.
authors: Jiing-Chyuan
authors: JC
authors: Luo
authors: Department of Medicine, National Yang-Ming University, School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Yen-Ling
authors: YL
authors: Peng
authors: Department of Medicine, National Yang-Ming University, School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Tseng-Shing
authors: TS
authors: Chen
authors: Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University, School of Medicine, Taipei, Taiwan.
authors: Teh-Ia
authors: TI
authors: Huo
authors: Department of Medicine, National Yang-Ming University, School of Medicine, Taipei, Taiwan; Endoscopic Center for Diagnosis and Therapy, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Healthcare and Management Center, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Ming-Chih
authors: MC
authors: Hou
authors: Department of Medicine, National Yang-Ming University, School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Hui-Chun
authors: HC
authors: Huang
authors: Department of Medicine, National Yang-Ming University, School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Han-Chieh
authors: HC
authors: Lin
authors: Department of Medicine, National Yang-Ming University, School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Fa-Yauh
authors: FY
authors: Lee
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D000077144:Clopidogrel; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013276:Stomach Ulcer / Q000188:drug therapy*; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives*; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage
chemical_list: D010975:Platelet Aggregation Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000077144:Clopidogrel; D048049:Extracellular Signal-Regulated MAP Kinases; D013988:Ticlopidine
keywords: angiogenesis; clopidogrel; extracellular signal-regulated kinase (ERK); gastric ulcer healing; vascular endothelial growth factor