title: A novel CXCR4 antagonist derived from human SDF-1beta enhances angiogenesis in ischaemic mice.
abstract: OBJECTIVE
  The effects on angiogenesis of a novel CXC chemokine receptor 4 (CXCR4) antagonist, SDF-1betaP2G, derived from human stromal cell-derived factor-1beta (SDF-1beta), were examined in a model of hind limb ischaemia in mice.
  
  
  RESULTS
  The antagonistic activities of SDF-1betaP2G against CXCR4 were evaluated in vitro and in vivo and compared with phosphate-buffered saline and AMD3100 (a small bicyclam antagonist of SDF-1). Angiogenesis, muscle regeneration and the expression of pro-angiogenic factors were evaluated in ischaemic gastrocnemius muscles. Distant toxic effects of SDF-1betaP2G were evaluated by inflammatory and apoptotic markers. SDF-1betaP2G induced CXCR4 internalization and competitively inhibited the chemotaxis of SDF-1beta but did not mediate migration, calcium influx, or the phosphorylation of Akt and extracellular signal-regulated kinase in cultured T-lymphoblastic leukaemia cells or H9C2 cells. SDF-1betaP2G enhanced blood flow, angiogenesis, and muscle regeneration in ischaemic hind limbs, and the enhancement was significantly better than that of AMD3100. Markers of angiogenesis and progenitor cell migration, including phosphorylated Akt, vascular endothelial growth factor (VEGF), SDF-1 and CXCR4, were up-regulated by SDF-1betaP2G and co-localized with CD31-positive cells. Neutralization of VEGF with its specific antibody abolished SDF-1betaP2G-induced blood reperfusion and angiogenesis. No apparent inflammatory and apoptotic effects were found in heart, liver, kidneys, and testes after SDF-1betaP2G administration.
  
  
  CONCLUSIONS
  Our findings indicate that the novel CXCR4 antagonist, SDF-1betaP2G, can efficiently enhance ischaemic angiogenesis, blood flow restoration, and muscle regeneration without apparent adverse effects, most likely through a VEGF-dependent pathway.
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical College, Chashan College Park, Wenzhou 325035, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
authors.forename: Hongwei
authors.initials: H
authors.lastname: Shao
authors.forename: Chuanlin
authors.initials: C
authors.lastname: Ding
authors.forename: Gavin E
authors.initials: GE
authors.lastname: Arteel
authors.forename: Keith A
authors.initials: KA
authors.lastname: Webster
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004926:Escherichia coli; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D007511:Ischemia / Q000188:drug therapy*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000096:biosynthesis; D012038:Regeneration / Q000187:drug effects*; D012039:Regional Blood Flow / Q000187:drug effects*; D015854:Up-Regulation
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D011994:Recombinant Proteins