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

摘要

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.