title: Induction of angiogenesis and modulation of vascular endothelial growth factor receptor-2 by simvastatin after traumatic brain injury.
abstract: BACKGROUND
  Our previous studies demonstrated that simvastatin reduced neuronal death, increased neurogenesis, and promoted functional recovery after traumatic brain injury (TBI).
  
  
  OBJECTIVE
  To investigate the effect of simvastatin on angiogenesis after TBI and the related signaling pathways.
  
  
  METHODS
  Saline or simvastatin (1 mg/kg) was administered orally to rats starting at day 1 after TBI or sham surgery and then daily for 14 days. Rats were sacrificed at 3 and 14 days after treatment. Brain sections and tissues were prepared for immunohistochemical staining, enzyme-linked immunosorbent assay, and Western blot analysis. Cultured rat brain microvascular endothelial cells were subjected to oxygen-glucose deprivation followed by immunocytochemical staining with phallotoxins and vascular endothelial growth factor receptor-2 (VEGFR-2). Western blot analysis was carried out to examine the simvastatin-induced activation of the v-akt murine thymoma viral oncogene homolog (Akt) signaling pathway. The expression of VEGFR-2 was detected by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Simvastatin significantly increased the length of vascular perimeter, promoted the proliferation of endothelial cells, and improved the sensorimotor function after TBI. Simvastatin stimulated endothelial cell tube formation after oxygen-glucose deprivation in vitro. VEGFR-2 expression in both brain tissues and cultured rat brain microvascular endothelial cells was enhanced after simvastatin treatment, which may be modulated by activation of Akt. Akt-dependent endothelial nitric oxide synthase phosphorylation was also induced by simvastatin in vivo and in vitro.
  
  
  CONCLUSIONS
  Simvastatin augments TBI-induced angiogenesis in the lesion boundary zone and hippocampus and improves functional recovery. Simvastatin also promotes angiogenesis in vitro. These beneficial effects on angiogenesis may be related to simvastatin-induced activation of the VEGFR-2/Akt/endothelial nitric oxide synthase signaling pathway.
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, USA.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Wu
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.forename: Dunyue
authors.initials: D
authors.lastname: Lu
authors.forename: Changsheng
authors.initials: C
authors.lastname: Qu
authors.forename: Ye
authors.initials: Y
authors.lastname: Xiong
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.forename: Asim
authors.initials: A
authors.lastname: Mahmood
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D002460:Cell Line; D002478:Cells, Cultured; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism* / Q000502:physiology
chemical_list: D042501:Angiogenic Proteins; D019821:Simvastatin; D040301:Vascular Endothelial Growth Factor Receptor-2