title: Norepinephrine stimulates mobilization of endothelial progenitor cells after limb ischemia.
abstract: OBJECTIVE
  During several pathological processes such as cancer progression, thermal injury, wound healing and hindlimb ischemia, the mobilization of endothelial progenitor cells (EPCs) mobilization was enhanced with an increase of sympathetic nerve activity and norepinephrine (NE) secretion, yet the cellular and molecular mechanisms involved in the effects of NE on EPCs has less been investigated.
  
  
  RESULTS
  EPCs from BMs, peripheral circulation and spleens, the VEGF concentration in BM, skeletal muscle, peripheral circulation and spleen and angiogenesis in ischemic gastrocnemius were quantified in mice with hindlimbs ischemia. Systemic treatment of NE significantly increased EPCs number in BM, peripheral circulation and spleen, VEGF concentration in BM and skeletal muscle and angiogenesis in ischemic gastrocnemius in mice with hind limb ischemia, but did not affair VEGF concentration in peripheral circulation and spleen. EPCs isolated from healthy adults were cultured with NE in vitro to evaluate proliferation potential, migration capacity and phosphorylations of Akt and eNOS signal moleculars. Treatment of NE induced a significant increase in number of EPCs in the S-phase in a dose-dependent manner, as well as migrative activity of EPCs in vitro (p<0.05). The co-treatment of Phentolamine, I127, LY294002 and L-NAME with NE blocked the effects of NE on EPCs proliferation and migration. Treatment with NE significantly increased phosphorylation of Akt and eNOS of EPCs. Addition of phentolamine and I127 attenuated the activation of Akt/eNOS pathway, but metoprolol could not. Pretreatment of mice with either Phentolamine or I127 significantly attenuated the effects of NE on EPCs in vivo, VEGF concentration in BM, skeletal muscle and angiogenesis in ischemic gastrocnemius, but Metoprolol did not.
  
  
  CONCLUSIONS
  These results unravel that sympathetic nervous system regulate EPCs mobilization and their pro-angiogenic capacity via α adrenoceptor, β 2 adrenoceptor and meanwhile Akt/eNOS signaling pathway.
authors.affiliation: Department of Cardiology, Wuhan General Hospital of Guangzhou Military, Wuhan, Hubei, China; Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Qijun
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Wuhan General Hospital of Guangzhou Military, Wuhan, Hubei, China.
authors.forename: Shifang
authors.initials: S
authors.lastname: Ding
authors.affiliation: Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Zonggui
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D066026:Endothelial Progenitor Cells / Q000502:physiology*; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007511:Ischemia / Q000097:blood / Q000473:pathology*; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology / Q000502:physiology*; D010646:Phentolamine / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D008790:Metoprolol; D009638:Norepinephrine; D010646:Phentolamine