Nitric oxide inhibits neointimal hyperplasia following vascular injury via differential, cell-specific modulation of SOD-1 in the arterial wall

Superoxide (O-2(center dot-)) promotes neointimal hyperplasia following arterial injury. Conversely, nitric oxide ((NO)-N-center dot) inhibits neointimal hyperplasia through various cell-specific mechanisms, including redox regulation. What remains unclear is whether NO exerts cell-specific regulation of the vascular redox environment following arterial injury to inhibit neointimal hyperplasia. Therefore, the aim of the present study was to assess whether (NO)-N-center dot exerts cell-specific, differential modulation of O-2(center dot-) levels throughout the arterial wall, establish the mechanism of such modulation, and determine if it regulates (NO)-N-center dot-dependent inhibition of neointimal hyperplasia. In vivo, (NO)-N-center dot increased superoxide dismutase-1 (SOD-1) levels following carotid artery balloon injury in a rat model. In vitro, (NO)-N-center dot increased SOD-1 levels in vascular smooth muscle cells (VSMC), but had no effect on SOD-1 in endothelial cells or adventitial fibroblasts. This SOD-1 increase was associated with an increase in sod1 gene expression, increase in SOD-1 activity, and decrease in O-2(center dot-) levels. Lastly, to determine the role of SOD-1 in (NO)-N-center dot-mediated inhibition of neointimal hyperplasia, we performed the femoral artery wire injury model in wild type and SOD-1 knockout (MO) mice, with and without (NO)-N-center dot. Interestingly, NO inhibited neointimal hyperplasia only in wild type mice, with no effect in SOD-1 MO mice. In conclusion, these data show the cell-specific modulation of O-2(center dot-) by (NO)-N-center dot through regulation of SOD-1 in the vasculature, highlighting its importance on the inhibition of neointimal hyperplasia. These results also shed light into the mechanism of (NO)-N-center dot-dependent redox balance, and suggest a novel VSMC redox target to prevent neointimal hyperplasia. Published by Elsevier Inc.