CD8+ T‐Cell Deletion Suppressed the Development of Injury‐Induced Experimental Neointimal Hyperplasia in Mice With or Without Chronic Stress

ABSTRACT Chronic stress exacerbates cardiovascular injury and remodeling. Given the pivotal roles that cytotoxic CD8 + T cells play in pathobiology, we investigated potential role(s) of CD8 + T cells in stress‐related vascular remodeling in a mouse carotid injury model. Eight‐week‐old male wild‐type (CD8a +/+ ) and CD8a knockout (CD8a −/− ) mice underwent carotid artery ligation plus cuff placement (L + C) with or without being subjected to chronic stress. At surgery conducted 2 weeks later, L + C alone had significantly promoted carotid neointimal hyperplasia and induced an extensive infiltration of CD8 + T cells into injured vascular tissues. Chronic stress further exacerbated neointimal formation and CD8 + T‐cell infiltration. Genetically deleting CD8 + T cells significantly attenuated neointimal hyperplasia, collagen deposition, and proliferative PCNA‐positive cells and reduced CD68‐positive macrophage infiltration, the expressions of inflammatory genes (AT1R, galectin‐3, MCP‐1, VCAM‐1, ICAM‐1) and extracellular matrix‐remodeling enzyme genes (MMP‐2, MMP‐9, cathepsin S, cathepsin K), and proliferative signaling‐pathway proteins (p‐Akt, p‐p38, p‐mTOR). Data from interferon (IFN)‐γ knockout (IFN‐γ −/− ) mice administered an IFN‐γ‐neutralizing antibody or an adoptive transfer of CD8 + T cells from IFN‐γ +/+ mice or IFN‐γ −/− mice further confirmed the CD8 + T‐cell deletion‐mediated protective effects against experimental neointimal hyperplasia in response to stress and injury. In vitro vascular smooth muscle cell experiments revealed that the cell migration and invasion abilities and mTOR/Akt signaling were sensitive to 5% stress serum from CD8a +/+ mice. CD8 + T‐cell deletion thus appears to ameliorate vascular remodeling, suggesting that genetic CD8 + T‐cell modification might be a promising therapeutic target for managing proliferative vascular diseases in animals under chronic stress conditions.