A central role for nicotinic cholinergic regulation of growth factor-induced endothelial cell migration

Martin K.C. Ng, Jenny Wu, Edwin Chang, Bing Yin Wang, Regina Katzenberg-Clark, Akiko Ishii-Watabe, John P. Cooke

Research output: Contribution to journalArticle

69 Scopus citations

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. METHODS AND 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.

Original languageEnglish (US)
Pages (from-to)106-112
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume27
Issue number1
DOIs
StatePublished - Jan 2007

Keywords

  • Angiogenesis
  • Endothelium
  • Fibroblast growth factor
  • Nicotine
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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