on November 2, 2006
Published online before print November 2, 2006, doi: 10.1161/01.ATV.0000251517.98396.4a
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Submitted on April 6, 2006
Accepted on October 16, 2006
A Central Role for Nicotinic Cholinergic Regulation of Growth Factor-Induced Endothelial Cell Migration
Martin K.C. Ng ;
From the Department of Medicine (M.K.C.N., J.W., E.C., B.-y.W., R.K.-C., A.I.-W., J.P.C.), Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif.; and the Department of Cardiology (M.K.C.N.), Royal Prince Alfred Hospital, Sydney, NSW, Australia.
* To whom correspondence should be addressed. E-mail: john.cooke{at}stanford.edu.
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.
Key words: nicotine • angiogenesis • endothelium • vascular endothelial growth factor • fibroblast growth factor
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