title: Sitagliptin therapy enhances the number of circulating angiogenic cells and angiogenesis-evaluations in vitro and in the rat critical limb ischemia model.
abstract: OBJECTIVE
  We tested the hypothesis that sitagliptin is capable of increasing blood flow in the rat critical limb ischemia (CLI) model by enhancement of angiogenesis.
  
  
  METHODS
  Adipose tissue from adult-male Fischer 344 rats (n = 6) were cultured in endothelial progenitor cell culture medium for 14 d with (25 μmol/L) or without sitagliptin. CLI was induced by ligation of the left femoral artery. Rats (n = 32) were equally separated into four groups: untreated controls (group 1), sitagliptin (4 mg/kg per day; group 2), CLI (group 3) and CLI with sitagliptin (group 4).
  
  
  RESULTS
  In vitro, 7 and 14 d after cell culture, endothelial progenitor cell biomarkers assessed by flow cytometry (Sca-1/CD31+, CXCR4+, c-kit+ and CD34+ cells) and Western blot (vascular endothelial growth factor, CXCR4 and stromal-derived factor [SDF]-1α) were remarkably higher in group 4 than in the other groups (all P < 0.01). In vivo, 2 and 14 d after the CLI procedure, circulating angiogenic cell (Sca-1/CD31+, Sca-1+ and CD31+) numbers were significantly higher in group 4 than in the other groups (all P < 0.001). Additionally, the messenger RNA and protein expression of angiogenic biomarkers (CXCR4, SDF-1α and vascular endothelial growth factor), immunofluorescent staining of angiogenic cells (CXCR4+, SDF-1α+, CD31+, von Willebrand factor + cells) and immunohistochemical staining of small vessel numbers in the ischemic area were significantly higher in group 4 than in the other groups (all P < 0.01). Furthermore, laser Doppler showed that the ratio of ischemic/normal blood flow was remarkably higher group 4 than in group 3 by days 14 and 28 after the CLI procedure (all P < 0.01).
  
  
  CONCLUSIONS
  Sitagliptin therapy enhances circulating angiogenic cell numbers, angiogenesis and blood flow in the CLI area.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Sarah
authors.initials: S
authors.lastname: Chua
authors.forename: Jiunn-Jye
authors.initials: JJ
authors.lastname: Sheu
authors.forename: Yung-Lung
authors.initials: YL
authors.lastname: Chen
authors.forename: Li-Teh
authors.initials: LT
authors.lastname: Chang
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.forename: Steve
authors.initials: S
authors.lastname: Leu
authors.forename: Hsin-Ching
authors.initials: HC
authors.lastname: Sung
authors.forename: Tzu-Hsien
authors.initials: TH
authors.lastname: Tsai
authors.forename: Sheng-Ying
authors.initials: SY
authors.lastname: Chung
authors.forename: Kuo-Ho
authors.initials: KH
authors.lastname: Yeh
authors.forename: Chung-Lung
authors.initials: CL
authors.lastname: Cho
authors.forename: Ying-Hsien
authors.initials: YH
authors.lastname: Kao
authors.forename: Hon-Kan
authors.initials: HK
authors.lastname: Yip
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006614:Hindlimb / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D000068900:Sitagliptin Phosphate; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D011719:Pyrazines; D014230:Triazoles; D000068900:Sitagliptin Phosphate
keywords: angiogenesis; endothelial progenitor cells; laser Doppler blood flow; sitagliptin