Smooth muscle cell-specific knockout of interferon gamma (IFN-γ) receptor attenuates intimal hyperplasia via STAT1-KLF4 activation.

Abstract Background Intimal hyperplasia is a main contributor to in-stent restenosis. Previous researches have shown that interferon-gamma (IFN-γ), a pleiotropic pro-inflammatory factor, plays a pathological role in intimal hyperplasia. However, the specific role and molecular mechanism of vascular smooth muscle cells (VSMCs)-derived IFN-γ receptor in intimal hyperplasia remains unknown. Methods We examined the distribution of IFN-γ receptor in human restenosis arteries. Then, the role of IFN-γ receptor in intimal hyperplasia was detected using VSMC-specific IFN-γ receptor-knock out carotid ligation injury models. We performed immunostaining, transwell assay and EdU staining to identify the role of IFN-γ in VSMCs proliferation and migration. The effect of IFN-γ on VSMCs phenotype switching was also investigated. Finally, we evaluated whether the mechanism of IFN-γ on intimal hyperplasia is STAT1-KLF4 dependent. Results The distribution of IFN-γ receptor in human restenosis arteries with VSMC-rich neointima is eventually upregulated. Specific deletion of IFN-γ receptor exhibits thinner intima and lesser proliferating VSMCs. In vitro, treatment with IFN-γ promotes human aortic VSMC (HAVSMCs) proliferation and migration, whereas specifically knock out IFN-γ receptor results in the opposite effect. Deficiency of IFN-γ receptor regulates VSMCs phenotypic switching, such as upregulated contractile markers and downregulated proliferation markers. Mechanistic studies suggest that ablation of IFN-γ receptor prevents VSMCs proliferation, migration and dedifferentiation via STAT1-KLF4 activation. Conclusion These results reveal that knockout of VSMC-derived IFN-γ receptor potentiates neointimal hyperplasia by preventing VSMCs proliferation, migration and dedifferentiation. Our finding implies that targeting IFN-γ-STAT1-KLF4 signaling could provide a new therapeutic strategy to attenuate vessel restenosis.