title: Exendin-4 protects hindlimb ischemic injury by inducing angiogenesis.
abstract: Exendin-4, an analog of glucagon-like peptide-1, has shown to have beneficial effects on endothelial function, and was recently approved for the treatment of diabetes. In previous studies, we showed that exendin-4 induces angiogenesis in in vitro and ex vivo assays; in this study, we assessed the proangiogenic effects of exendin-4 in vivo using a mouse hindlimb ischemia model. Treatment with exendin-4 for three days mitigated hindlimb and gastrocnemius muscle fiber necrosis. Hindlimb perfusion was determined using indocyanine green fluorescence dynamics that showed, significantly higher blood flow rate to the ischemic hindlimbs in an exendin-4-treated group. Immunohistochemistry assay showed that exendin-4 increased CD31-positive areas in the gastrocnemius muscle of ischemic limbs. Furthermore, treatment of the hindlimbs of ischemic mice with exendin-4 increased vascular endothelial growth factor (VEGF) and phospho-extracellular signal-related kinase (ERK) on western blot analysis. Our data demonstrate that exendin-4 prevents hindlimb ischemic injury by inducing vessels via VEGF angiogenic-related pathways. These findings suggest that exendin-4 has potential as a therapeutic agent for vascular diseases that stimulate angiogenesis.
authors: Department of Anatomy and Neurobiology, Biomedical Science Institute, School of Medicine, Kyung Hee University, Republic of Korea.
authors: Hye-Min
authors: HM
authors: Kang
authors: Department of Anatomy and Neurobiology, Biomedical Science Institute, School of Medicine, Kyung Hee University, Republic of Korea.
authors: Inkyung
authors: I
authors: Sohn
authors: Department of Anatomy and Neurobiology, Biomedical Science Institute, School of Medicine, Kyung Hee University, Republic of Korea.
authors: Junyang
authors: J
authors: Jung
authors: Department of Anatomy and Neurobiology, Biomedical Science Institute, School of Medicine, Kyung Hee University, Republic of Korea.
authors: Joo-Won
authors: JW
authors: Jeong
authors: Department of Anatomy and Neurobiology, Biomedical Science Institute, School of Medicine, Kyung Hee University, Republic of Korea. Electronic address: psychan@khu.ac.kr.
authors: Chan
authors: C
authors: Park
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D000077270:Exenatide; D006439:Hemodynamics / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply / Q000293:injuries; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010455:Peptides / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014688:Venoms / Q000627:therapeutic use*
chemical_list: D043925:Angiogenesis Inducing Agents; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A; D014688:Venoms; C467480:vascular endothelial growth factor A, mouse; D000077270:Exenatide
keywords: Angiogenesis; Exendin-4; Fluorescence dynamics; Hindlimb ischemia; Vascular endothelial growth factor