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Nitric Oxide Decreases Neointimal Hyperplasia via Differential Regulation of Reactive Oxygen Species Throughout the Arterial Wall

Daniel A. Popowich, Janet Martinez, Vanessa R. Lee, Jozef Murar, Samer F. Najjar, Qun Jiang, Christopher P. Walsh, Melina R. Kibbe.
Northwestern University, Chicago, Ill.

OBJECTIVES: Reactive oxygen species (ROS) are known to increase throughout the arterial wall following injury. Major sources of ROS are the NADPH oxidases which produce superoxide (O2-). Our lab has demonstrated that periadventitial administration of nitric oxide (NO) to a balloon-injured rat carotid artery significantly reduces neointimal hyperplasia. The aim of this project was to study the effect of NO on ROS production within the arterial wall following injury. We hypothesize that differential regulation of ROS production and SOD-1 expression exists between the intima, media, and adventitia and this differential regulation and spatial orientation contributes to the decrease in neointimal hyperplasia observed in NO-treated arteries.

METHODS: Sprague Dawley rats underwent balloon injury to the carotid artery ± periadventitial application of NO (PROLI/NO). Vessels were evaluated at 3 and 14 days. O2- was detected using dihydroethidium fluorescence. Peroxynitrite (ONOO-) formation and SOD-1 expression was assessed using immunohistochemical staining. Apoptosis was assessed with TUNEL.

RESULTS: Although there was an increase in O2- in the adventitia of the injury + NO group, there was a striking absence of signal emanating from the media. This was also observed in the NO without injury group. ONOO- was unchanged with injury alone but was increased in the media and adventitia of NO-treated and injury + NO-treated groups. This same pattern was observed with SOD-1. An increase in O2- was seen in the endothelium of the injury and the NO-treated groups, but there were no differences in ONOO- or SOD-1. Significantly more adventitial cell apoptosis was seen in the NO alone and injury + NO compared to the injury alone group. Of note, cellularity was diminished in the media of all NO-treated groups.

CONCLUSIONS: These results suggest that periadventitial application of NO increases O2- production in the endothelium and adventitia but not the media. This may be because of the formation of ONOO- by the reaction of O2- with NO, and/or because of the increase in SOD-1. These data imply that not only are ROS important in the control of vascular remodeling, but their production and location within the vessel wall are differentially regulated and this impacts the development of neointimal hyperplasia following vascular injury.

AUTHOR DISCLOSURES: D.A. Popowich, None; J. Martinez, None; V.R. Lee, None; J. Murar, None; S.F. Najjar, None; Q. Jiang, None; C.P. Walsh, None; M.R. Kibbe, None.