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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:106.)
© 2007 American Heart Association, Inc.

Vascular Biology

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

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.

Correspondence to John P. Cooke, Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5406. 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.

Nicotine induces nicotinic acetylcholine receptor (nAChR)–dependent endothelial cell migration (ECM). nAChR antagonism also suppresses bFGF- and VEGF-induced ECM. ECM induced by nicotine, VEGF, or bFGF requires nAChR-dependent induction of thioredoxin activity via repression of the thioredoxin inhibitor, TXNIP. Therefore growth factor–induced ECM, a key angiogenesis event, requires nAChR activation.

Key Words: nicotine • angiogenesis • endothelium • vascular endothelial growth factor • fibroblast growth factor

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