Adventitial contributions of the extracellular signal-regulated kinase and Akt pathways to neointimal hyperplasia

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 was to characterize the effect of sex, hormones, and NO on the extracellular signalregulated kinase (ERK) and Akt signaling pathways after arterial injury. Methods: Male and female SpragueDawley rats underwent castration or sham surgery. Two weeks later, they underwent carotid artery balloon injury. Treatment groups included the following: control, injury, and injury + 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO) (n = 5 per group). Arteries were harvested 2 weeks after injury and assessed for phospho-ERK (pERK) and phospho-Akt (pAkt) expression. Results: After injury, more pERK and pAkt activity was seen in the adventitia than media in both sexes, regardless of hormone status (P <.05). In hormonally intact males, NO further increased pERK (44%) and pAkt (120%) after injury (P <.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. Conclusions: After 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.