on November 2, 2006
Published online before print November 2, 2006, doi: 10.1161/01.ATV.0000251517.98396.4a
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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
This article has been cited by other articles:
 |
|
 |
|
  T. E. Tipple, S. E. Welty, L. D. Nelin, J. M. Hansen, and L. K. Rogers Alterations of the Thioredoxin System by Hyperoxia: Implications for Alveolar Development Am. J. Respir. Cell Mol. Biol., November 1, 2009; 41(5): 612 - 619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Mukherjee and S G Martin The thioredoxin system: a key target in tumour and endothelial cells Br. J. Radiol., October 1, 2008; 81(Special_Issue_1): S57 - S68. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Celermajer and M. K.C. Ng Where There's Smoke... J. Am. Coll. Cardiol., May 6, 2008; 51(18): 1772 - 1774. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kiuchi, M. Matsuoka, J. C. Wu, R. Lima e Silva, M. Kengatharan, M. Verghese, S. Ueno, K. Yokoi, N. H. Khu, J. P. Cooke, et al. Mecamylamine Suppresses Basal and Nicotine-Stimulated Choroidal Neovascularization Invest. Ophthalmol. Vis. Sci., April 1, 2008; 49(4): 1705 - 1711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. P. Sieveking, A. Buckle, D. S. Celermajer, and M. K.C. Ng Strikingly different angiogenic properties of endothelial progenitor cell subpopulations: insights from a novel human angiogenesis assay. J. Am. Coll. Cardiol., February 12, 2008; 51(6): 660 - 668. [Abstract] [Full Text] [PDF]
|
|