title: Endothelial progenitor cells participate in nicotine-mediated angiogenesis.
abstract: OBJECTIVE
  We aimed to determine the role of endothelial progenitor cells (EPCs) in cholinergic angiogenesis.
  
  
  BACKGROUND
  Recently, we provided evidence for a new angiogenic pathway mediated by endothelial nicotinic acetylcholine receptors (nAChR). Increasing evidence suggests that circulating EPCs also contribute to postnatal neovascularization by homing to sites of neovascularization, a process termed postnatal vasculogenesis. Therefore, we investigated whether nAChR activation increases mobilization and/or recruitment of EPCs to a site of angiogenesis.
  
  
  METHODS
  To identify EPCs from reservoirs both inside and outside of the bone marrow and to avoid the adverse effects of total body irradiation, we employed a murine parabiosis model with tie-2-LacZ FvB/N mice connected to wild-type FvB/N mice and induced unilateral hind limb ischemia in the wild-type animal.
  
  
  RESULTS
  Administration of nicotine increased capillary density in the ischemic hind limb, and increased soluble Kit ligand plasma levels. The effect of systemic administration was greater than that of local delivery of nicotine (45% vs. 76% increase in capillary density by comparison to vehicle control, intramuscular vs. oral administration of nicotine; p < 0.05). Ischemia-induced incorporation of EPC in the control group was rare, but was increased 5-fold by systemic administration of nicotine. Exposure to nicotine in vitro increased EPC count and EPC transmigration. Finally, systemic administration of nicotine increased EPC number in the bone marrow and spleen during hind limb ischemia.
  
  
  CONCLUSIONS
  Nicotine treatment increased the number of EPCs in the bone marrow and spleen, and increased their incorporation into the vasculature of ischemic tissue. Administration of nicotine increased markers of EPC mobilization. This study indicates that the known angiogenic effect of nicotine may be mediated in part by mobilization of precursor cells.
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
authors.forename: Edwin
authors.initials: E
authors.lastname: Chang
authors.forename: Alexandra
authors.initials: A
authors.lastname: Aicher
authors.forename: John P
authors.initials: JP
authors.lastname: Cooke
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage*; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects*; D005260:Female; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D009538:Nicotine / Q000008:administration & dosage*; D010227:Parabiosis; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013234:Stem Cells / Q000187:drug effects
chemical_list: D043925:Angiogenesis Inducing Agents; D011978:Receptors, Nicotinic; D009538:Nicotine