Nicotine-induced vascular endothelial growth factor release via the EGFR-ERK pathway in rat vascular smooth muscle cells.
Cigarette smoke has been firmly established as an independent risk factor for atherosclerosis and other vascular diseases. The proliferation and migration of vascular smooth muscle cells (VSMC) induced by growth factors have been proposed to play an important role in the progression of atherosclerosis. In the present study, we investigated the effects of nicotine, which is one of the important constituents of cigarette smoke, on vascular endothelial growth factor (VEGF) release, in rat VSMC. The stimulation of cells with nicotine resulted in a time- and concentration-dependent release of VEGF. Hexamethonium, an antagonist of nicotinic acetylcholine receptor (nAChR), inhibited nicotine-induced VEGF release. We next investigated the mechanisms by which nicotine induces VEGF release in the cells. The nicotine-induced VEGF release was inhibited by treatment with U0126, a selective inhibitor of MEK, which attenuated the nicotine-induced ERK phosphorylation. Nicotine induced a transient phosphorylation of ERK. Furthermore, AG1478, a selective inhibitor of epidermal growth factor receptor (EGFR) kinase, inhibited nicotine-induced ERK phosphorylation and VEGF release. These data suggest that nicotine releases VEGF through nAChR in VSMC. Moreover, VEGF release induced by nicotine is mediated by an EGFR-ERK pathway in VSMC. VEGF may contribute to the risk of cardiovascular diseases in cigarette smokers.
Kanda
Yasunari
Y
Department of Pharmacology, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama 359-8513, Japan. kanda@ndmc.ac.jp
Watanabe
Yasuhiro
Y
D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D018738:Hexamethonium / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011799:Quinazolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D002070:Butadienes; D004791:Enzyme Inhibitors; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D009570:Nitriles; D011799:Quinazolines; D011978:Receptors, Nicotinic; D020032:Tyrphostins; C113580:U 0126; D042461:Vascular Endothelial Growth Factor A; C101044:RTKI cpd; D018738:Hexamethonium; D009538:Nicotine; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases