Abstract
Neointimal hyperplasia is the leading cause of restenosis after endovascular interventions. It is characterized by the accumulation of myofibroblast-like cells and extracellular matrix in the innermost layer of the wall and is exacerbated by inflammation. Monocytes from either young or aged rats were applied perivascularly to injured vascular walls of young recipient animals. Monocytes from aged rats, but not young donors, increased neointima thickness. Accordingly, the gene expression profiles of CD11b+ monocytes from aged rats showed significant up-regulation of genes involved in cellular adhesion, lipid degradation, cytotoxicity, differentiation, and inflammation. These included cadherin 13 (Cdh13), colony stimulating factor 1 (Csf1), chemokine C-X-C motif ligand 1 (Cxcl1), endothelial cell-selective adhesion molecule (Esam), and interferon gamma (Ifng). In conclusion, our results suggest that the increased inflammatory and adhesive profile of monocytes contributes to pathological wall remodeling in aged-related vascular diseases.
Highlights
Activation of monocytes and differentiation into macrophages are major steps in vascular proliferative diseases like atherosclerosis and restenosis [1,2,3]
The total percentage of monocytes in peripheral blood mononuclear cells (PBMC) was significantly higher in aged rats compared to young animals (14.4 ± 2.0 vs. 6.6 ± 0.2%, p = 0.02; Figure 1B), as previously reported [13], while the opposite was observed for peripheral lymphocytes, not statistically significant (43.1 ± 12.3 vs. 49.4 ± 21.2%, p = 0.8)
In this work we demonstrated that 1) aging causes monocytosis in rats, 2) monocytes from aged animals exacerbate neointimal hyperplasia (NIH), and 3) aging induces profound differences in monocyte gene expression
Summary
Activation of monocytes and differentiation into macrophages are major steps in vascular proliferative diseases like atherosclerosis and restenosis [1,2,3]. Monocytes/macrophages produce growth factors that stimulate vascular smooth muscle cell (VSMC) differentiation and growth [4, 5], while contributing to the deposition of extracellular matrix (ECM) to facilitate immune cell infiltration [6, 7] and myofibroblastic migration from the adventitia [8]. It is believed that agedrelated changes in monocyte numbers and phenotypes contribute to the development of vascular diseases in the elderly [9,10,11,12]. We found that monocytes/macrophages in aged rats are more pro-inflammatory and adhesive than in younger animals, which in part explains the increased number of macrophages after vascular injury in aged vasculature [6].
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