• Robert M Starke, Lauren A Pace, Crissey L Pascale, Dale Ding, Muhammad Ali, David M Hasan, Gary Owens, and Aaron S Dumont.
• Neurosurgery. 2015 Aug 1;62 Suppl 1:196.

IntroductionTo investigate the role of cigarette smoke exposure (CSE) in the regulation of cerebral smooth muscle cell (SMC) phenotypic modulation in a NAPDH (NOX)-dependent manner and its effect on cerebral aneurysm (CA) formation and rupture.MethodsCultured rat cerebral vascular SMCs and mice following cerebral aneurysm induction surgery underwent CSE during both in vitro and in vivo experiments.ResultsIn cultured cerebral vascular SMCs, CSE increased expression of NOX-1 and reactive oxygen species (ROS) as early as 4 hours after treatment, with maximal upregulation of proinflammatory/matrix remodeling genes (MCP-1, MMPs, TNF-α, IL-1β, NF-κB, KLF4) at 24 hours. SMC contractile genes (SM-a-actin, SM-22a, SM-MHC) and myocardin were maximally decreased at 24 hours. Inhibition with superoxide dismutase and viral Ad/AS-NOX1 decreased CSE-induced upregulation of NOX-1 and inflammatory genes and downregulation of SMC contractile genes and myocardin. NOX p47phox-/- mice and those pretreated with apocynin had significantly decreased incidence of CA formation and rupture. Additionally, mice exposed to cigarette smoke had an increased incidence of CA formation and rupture, which was diminished with apocynin pretreatment. NOX-1 protein, mRNA, and ROS were elevated in animals exposed to cigarette smoke, and in unruptured and furthermore in ruptured CAs.ConclusionCSE initiates oxidative stress-induced phenotypic modulation of SMCs leading to CA formation and rupture. These molecular changes implicate oxidative stress in the pathogenesis of CAs and may provide a potential target for future therapeutic strategies.

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