Adventitial Contributions of the ERK and Akt Pathways to Neointimal Hyperplasia

, Abstract Background— We recently reported that the efficacy of nitric oxide (NO) appears to be based on both sex and hormone status. The mechanism responsible for this differential efficacy is unknown. The aim of this study is to characterize the effect of sex, hormones, and NO on the ERK and Akt signaling pathways following arterial injury. Methods— Male and female Sprague Dawley rats underwent castration or sham surgery. Two weeks later, they underwent carotid artery balloon injury. Treatment groups included: control, injury, and injury+PROLI/NO (n=5/group). Arteries were harvested 2 weeks post-injury and assessed for pERK and pAkt expression. Results— Following injury, more pERK and pAkt activity was seen in the adventitia than media in both sexes, regardless of hormone status (P<0.05). In hormonally-intact males, NO further increased pERK (44%) and pAkt (120%) after injury (P<0.001). Castration attenuated the effects of NO. In hormonally-intact females, NO caused the opposite pattern with pERK activity but did not affect pAkt activity. Conclusion— Following arterial injury, ERK and Akt activity is significantly greater in the adventitia than the media, and depends on sex, hormone status, and NO. Understanding adventitial regulation of proliferative signaling pathways will allow the development of targeted therapies for neointimal hyperplasia. Our lab and others have shown that nitric oxide (NO) is a potent inhibitor of neointimal development. (4) We recently showed that NO

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