ABSTRACT: BACKGROUND AND PURPOSE: Current treatment modalities for critical limb ischemia (CLI) still make difficult progress, concepts on therapeutic vasculogenesis may open a new field on the treatment of CLI. This study is to study the DPP-4 inhibitor, sitagliptin, originally used as a hypoglycemic agent, in therapeutic potential of vasculogenesis in vivo. EXPERIMENTAL APPROACH: Sitagliptin were administered daily to C57CL/B6 mice and eGFP transgenic mouse bone marrow-transplanted ICR mice that had undergone hind limb ischemic surgery. Laser Doppler imaging and flowcytometry was used to evaluate the degree of neo-vasculogenesis and circulating levels of EPCs, respectively. Cell surface marker of EPCs and endothelial nitric oxide synthase (eNOS) in vessels were studies. KEY RESULTS: Mice that received sitagliptin with elevated plasma glucagon-like peptide-1 (GLP-1) levels, decreased plasma dipeptidyl peptidase-4 (DDP-4) concentration, as well as augmented ischemia induced increases in stromal cell-derived factor-1 (SDF-1) in a dose-dependent manner. Blood flow in the ischemic limb was significantly improved in mice treated with sitagliptin. Circulating levels of EPCs were also increased after sitagliptin treatment. Sitagliptin administration enhanced expression of CD 34 and eNOS in ischemia muscle. Additionally, sitagliptin promoted EPC mobilization and homing to ischemic tissue in eGFP transgenic mouse bone marrow-transplanted ICR mouse. CONCLUSIONS AND IMPLICATIONS: Circulating EPC levels and neo-vasculogenesis were augmented by DPP-4 inhibitor, which was dependent of eNOS-related pathway. The results indicate the therapeutic vasculogenesis potential of the DPP-4 inhibitor sitagliptin in a mouse hind limb ischemia model. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
British Journal of Pharmacology 07/2012; · 4.41 Impact Factor