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

• Nitric oxide increases SOD-1 protein levels in vascular smooth muscle cells, but not in endothelial cells or adventitial fibroblasts.
• The
• NO-dependent increase in the SOD-1 levels is preceded by an increase in gene expression; it also correlates with an increase in SOD-1 activity and a decrease in superoxide levels.
• Nitric oxide is more effective at inhibiting the development of neointimal hyperplasia after wire femoral injury in wild-type mice than in SOD-1 knockout mice.
• Nitric oxide regulates vascular smooth muscle cell proliferation by differentially regulating the redox environment in these cells.

Superoxide (O2
• −) promotes neointimal hyperplasia following arterial injury. Conversely, nitric oxide (
• NO) 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 exerts cell-specific, differential modulation of O2
• − levels throughout the arterial wall, establish the mechanism of such modulation, and determine if it regulates
• NO-dependent inhibition of neointimal hyperplasia. In vivo,
• NO increased superoxide dismutase-1 (SOD-1) levels following carotid artery balloon injury in a rat model. In vitro,
• NO 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 O2
• − levels. Lastly, to determine the role of SOD-1 in
• NO-mediated inhibition of neointimal hyperplasia, we performed the femoral artery wire injury model in wild type and SOD-1 knockout (KO) mice, with and without
• NO. Interestingly,
• NO inhibited neointimal hyperplasia only in wild type mice, with no effect in SOD-1 KO mice. In conclusion, these data show the cell-specific modulation of O2
• − by
• NO 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-dependent redox balance, and suggest a novel VSMC redox target to prevent neointimal hyperplasia.

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