Roles of Nicotine in the Development of Intracranial Aneurysm Rupture

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 alpha 7 subunits (alpha 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 alpha 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 alpha 7*-nAChR-selective agonist significantly increased aneurysm rupture rate. Coexposure to an alpha 7*-nAChR antagonist abolished nicotine's deleterious effect. In addition, nicotine's promotion of aneurysm rupture was absent in smooth muscle cell-specific alpha 7*-nAChR subunit knockout mice but not in mice lacking alpha 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. alpha 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 alpha 7*-nAChR. Visual Overview-An online visual overview is available for this article.