title: A central role for nicotinic cholinergic regulation of growth factor-induced endothelial cell migration.
abstract: OBJECTIVE
  An endothelial nicotinic acetylcholine receptor (nAChR) participates in atherogenesis and tumorigenesis by promoting neovascularization. To date, the mechanisms of nAChR-mediated angiogenesis and their relationship to angiogenic factors, eg, VEGF and bFGF, are unknown.
  
  
  RESULTS
  Nicotine induced dose-dependent human microvascular endothelial cell (HMVEC) migration, a key angiogenesis event, to an extent which was equivalent in magnitude to bFGF (10 ng/mL) but less than for VEGF (10 ng/mL). Unexpectedly, nAChR antagonism not only abolished nicotine-induced HMVEC migration but also abolished migration induced by bFGF and attenuated migration induced by VEGF. Transcriptional profiling identified gene expression programs which were concordantly regulated by all 3 angiogens (nicotine, VEGF, and bFGF), a notable feature of which includes corepression of thioredoxin-interacting protein (TXNIP), endogenous inhibitor of the redox regulator thioredoxin. Furthermore, TXNIP repression by all 3 angiogens induced thioredoxin activity. Silencing thioredoxin by small interference RNA abrogated all angiogen-induced migration while silencing TXNIP strongly induced HMVEC migration. Interestingly, nAChR antagonism abrogates growth factor (VEGF and bFGF)-mediated induction of thioredoxin activity.
  
  
  CONCLUSIONS
  Nicotine promotes angiogenesis via stimulation of nAChR-dependent endothelial cell migration. Furthermore, growth factor-induced HMVEC migration, a key angiogenesis event, requires nAChR activation--an effect mediated in part by nAChR-dependent regulation of thioredoxin activity.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Martin K C
authors.initials: MK
authors.lastname: Ng
authors.forename: Jenny
authors.initials: J
authors.lastname: Wu
authors.forename: Edwin
authors.initials: E
authors.lastname: Chang
authors.forename: Bing-yin
authors.initials: BY
authors.lastname: Wang
authors.forename: Regina
authors.initials: R
authors.lastname: Katzenberg-Clark
authors.forename: Akiko
authors.initials: A
authors.lastname: Ishii-Watabe
authors.forename: John P
authors.initials: JP
authors.lastname: Cooke
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D018722:Nicotinic Agonists; D034741:RNA, Small Interfering; D011978:Receptors, Nicotinic; C486715:TXNIP protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D013879:Thioredoxins; D009538:Nicotine