Roles of Nicotine in the Development of Intracranial Aneurysm Rupture

• Published in: Stroke (1970) Vol. 49; no. 10; pp. 2445 - 2452
• Main Authors: Kamio, Yoshinobu, Miyamoto, Takeshi, Kimura, Tetsuro, Mitsui, Kazuha, Furukawa, Hajime, Zhang, Dingding, Yokosuka, Kimihiko, Korai, Masaaki, Kudo, Daisuke, Lukas, Ronald J., Lawton, Michael T., Hashimoto, Tomoki
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.10.2018
• Subjects: alpha7 Nicotinic Acetylcholine Receptor - drug effects; Aneurysm, Ruptured - drug therapy; Animals; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Intracranial Aneurysm - drug therapy; Mice, Transgenic; Nicotine - pharmacology; Nicotinic Agonists - pharmacology; Receptors, Nicotinic - drug effects; Receptors, Nicotinic - genetics; Up-Regulation - drug effects; models, animal; nicotine; tobacco; intracranial aneurysm; α7 nicotinic acetylcholine receptor
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.118.021706

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 α7 subunits (α7*-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 α7*-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 α7*-nAChR–selective agonist significantly increased aneurysm rupture rate. Coexposure to an α7*-nAChR antagonist abolished nicotine’s deleterious effect. In addition, nicotine’s promotion of aneurysm rupture was absent in smooth muscle cell–specific α7*-nAChR subunit knockout mice but not in mice lacking α7*-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. α7*-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 α7*-nAChR.