CCL5 deficiency reduces neointima formation following arterial injury and thrombosis in apolipoprotein E-deficient mice. Issue 144 (August 2016) - Czepluch, Frauke S.
Abstract: Activated platelets secrete different chemokines, among others CCL5, thereby triggering inflammatory cell recruitment into the vessel wall. Here, we investigated how CCL5 deficiency influences vascular remodeling processes. Experiments were performed in apolipoprotein E and CCL5 double deficient (ApoE −/− × CCL5 −/− ) mice, using ApoE −/− × CCL5 +/+ mice as controls. The ferric chloride model was applied to induce thrombosis at the site of carotid artery injury within minutes and the formation of a smooth muscle cell-rich neointima within 3 weeks. In both groups, vascular injury resulted in thrombus formation. CCL5 deficiency did not alter thrombus resolution examined at day 7. Analysis at 21 days revealed that CCL5 absence was associated with a significant reduction in the neointima area (p < 0.05), neointima-to-media ratio (p < 0.05) and lumen stenosis (p < 0.05) compared to ApoE −/− × CCL5 +/+ mice. Immunohistochemical analysis of CCL5 receptors showed decreased CCR5 positive staining in ApoE −/− × CCL5 −/− mice (p < 0.01), whereas the amount of CCR1 (p = 0.053) and Mac2-positive macrophages (p < 0.05) was increased. The amount of SMA-positive smooth muscle cells was lower in ApoE −/− mice lacking CCL5 (p < 0.05). Positive staining for Krüppel-like factor 4 (KLF4), an atheroprotective transcription factor, was increased in the neointima of ApoE −/− × CCL5 −/− mice (p < 0.05) and found to co-localize with smooth muscle cells. In summary, CCL5 deficiency resulted in reduced neointima formation after carotid artery injury and thrombosis. Hemodynamic and histochemical analyses suggested that this was not due to differences in thrombus formation or resolution. Possibly, the atheroprotective effect of CCL5 deficiency is mediated by KLF4 upregulation in smooth muscle cells. Highlights: We examined how CCL5 deficiency affects postthrombotic vascular remodeling. CCL5 deficiency decreased neointima formation after carotid injury in ApoE −/− mice. Reduced neointima formation was not the result of differences in thrombus formation. Atheroprotective effects of CCL5 deficiency may involve changes in KLF4 expression.