title: Paradoxical impairment of angiogenesis, endothelial function and circulating number of endothelial progenitor cells in DPP4-deficient rat after critical limb ischemia.
abstract: BACKGROUND
  We hypothesized that dipeptidyl peptidase-IV (DPP4) may impair angiogenesis, endothelial function, and the circulating number of endothelial progenitor cells (EPC) in a model of critical limb ischemia (CLI) through ligating the left femoral artery using DPP4-deficient rats.
  
  
  METHODS
  Adult male DPP4-deficient (DPP4(D)) rats (n = 18) were equally divided into CLI only (DPP4(D)-CLI) and CLI treated by granulocyte colony-stimulating factor (GCSF) (DPP4(D)-CLI-GCSF). For comparison, age-matched wild-type (WT) Fischer 344 rats (n = 18) were randomized into two groups receiving identical treatment compared to their DPP4-deficient counterparts and labeled as WT-CLI (n = 9) and WT-CLI-GCSF (n = 9), respectively.
  
  
  RESULTS
  The circulating number of EPCs (CD31(+), CD34(+), CD133, C-kit(+)) was significantly lower in DPP4-deficient than in WT rats on post-CLI days 1 and 4 (all P < 0.01). The ratio of ischemia/normal blood flow was remarkably lower in DPP4(D)-CLI-GCSF rats than in WT-CLI-GCSF animals on post-CLI Day 14 (all P < 0.01). Protein expressions of pro-angiogenic factors (endothelial nitric oxide synthase (eNOS), CXCR4, SDF-1α, vascular endothelial growth factor (VEGF)) were remarkably higher in WT-CLI than in DPP4(D)-CLI rats, and higher in WT-CLI-GCSF than in DPP4(D)-CLI-GCSF animals (all P < 0.01). Moreover, the numbers of small vessel in the ischemic area were substantially higher in WT-CLI-GCSF than in DPP4(D)-CLI-GCSF rats (P < 0.001). Furthermore, vasorelaxation and nitric oxide production of the normal femoral artery were significantly reduced in DPP4-deficient than in WT Fischer rats (all P < 0.01).
  
  
  CONCLUSIONS
  Contrary to our hypothesis, DPP4-deficient rats were inferior to age-matched WT Fischer rats in terms of angiogenesis, endothelial function, circulating EPC number and response to GCSF, suggesting a positive role of DPP4 in maintaining vascular function and tissue perfusion in this experimental setting.
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.forename: Steve
authors.initials: S
authors.lastname: Leu
authors.forename: Jiunn-Jye
authors.initials: JJ
authors.lastname: Sheu
authors.forename: Tzu-Hsien
authors.initials: TH
authors.lastname: Tsai
authors.forename: Hsin-Chin
authors.initials: HC
authors.lastname: Sung
authors.forename: Yung-Lung
authors.initials: YL
authors.lastname: Chen
authors.forename: Sheng-Ying
authors.initials: SY
authors.lastname: Chung
authors.forename: Sheung-Fat
authors.initials: SF
authors.lastname: Ko
authors.forename: Hsueh-Wen
authors.initials: HW
authors.lastname: Chang
authors.forename: Hon-Kan
authors.initials: HK
authors.lastname: Yip
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001783:Blood Flow Velocity / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005690:Galactose / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D019718:Receptors, CXCR4 / Q000378:metabolism; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000954:Antigens, Surface; D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D018819:Dipeptidyl Peptidase 4; D005690:Galactose