LAUSR

Background and Purpose— Tobacco cigarette smoking is considered to be a strong risk factor for intracranial aneurysmal rupture. Nicotine is a major biologically active constituent of tobacco products. Nicotine’s interactions with vascular cell nicotinic acetylcholine receptors containing &agr;7 subunits (&agr;7*-nAChR) are thought to promote local inflammation and sustained angiogenesis. In this study, using a mouse intracranial aneurysm model, we assessed potential contributions of nicotine exposure and activation of &agr;7*-nAChR to the development of aneurysmal rupture. Methods— Intracranial aneurysms were induced by a combination of deoxycorticosterone-salt induced hypertension and a single-dose elastase injection into cerebrospinal fluid in mice. Results— Exposure to nicotine or an &agr;7*-nAChR–selective agonist significantly increased aneurysm rupture rate. Coexposure to an &agr;7*-nAChR antagonist abolished nicotine’s deleterious effect. In addition, nicotine’s promotion of aneurysm rupture was absent in smooth muscle cell–specific &agr;7*-nAChR subunit knockout mice but not in mice lacking &agr;7*-nAChR on endothelial cells or macrophages. Nicotine treatment increased the mRNA levels of vascular endothelial growth factor, platelet-derived growth factor-B, and inflammatory cytokines. &agr;7*-nAChR antagonist reversed nicotine-induced upregulation of these growth factors and cytokines. Conclusions— Our findings indicate that nicotine exposure promotes aneurysmal rupture through actions on vascular smooth muscle cell &agr;7*-nAChR.