Knockout of CD8 Delays Reendothelialization and Accelerates Neointima Formation in Injured Arteries of Mouse via TNF-α Inhibiting the Endothelial Cells Migration

Abstract

ObjectiveDelayed or impaired reendothelialization is a major cause of stent thrombosis in the interventional treatment of coronary heart disease. T cells are involved in neointima formation of injured arteries. However, the regulated mechanism of reendothelialization and the role of CD8 T cell in reendothelialization are unclear.Methods and ResultsImmunofluorescence staining showed that CD8 positive cells were increased in wire injured femoral artery of mice. On day 21 after injury, elastin staining showed that knockout of CD8 (CD8−/−) significantly increased intimal thickness and a ratio of intima to media by 1.8 folds and 1.9 folds respectively in injured arteries. Evans blue staining showed that knockout of CD8 delayed the reendothelialization area on day 7 after injury (18.8±0.5% versus 42.1±5.6%, p<0.05). In vitro, a migration assay revealed that CD8−/− T cells co-cultured with WT macrophages significantly inhibited the migration of the endothelial cells (ECs); compared to CD4+ T cells, and CD8+ T cells could promote the ECs migration. Furthermore, real-time PCR analysis showed that knockout of CD8 increased the level of tumor necrosis factor α (TNF-α) in injured arteries and cytometric bead cytokine array showed that TNF-α was elevated in cultured CD8−/− T cells. Finally, a wound-healing assay showed that recombinant TNF-α significantly inhibited the migration of ECs.ConclusionOur study suggested that CD8+ T cells could promote the reendothelialization and inhibit the neointima formation after the artery wire injury, and this effect is at least partly dependent on decreasing TNF-α production promoting ECs migration.

Involvement of CD8+ T cell subsets in early response to vascular injury in patients with peripheral artery disease in vivo

“…Identification of possible CD8 T cell interactions with injured vascular wall, while novel in humans, is in line with studies showing the importance of CD8+T cells in the vascular injury response in mice [30, 31]. Interestingly, CD8 knockout increased neointimal formation and TNF levels in injured arteries and was also associated with delayed re-endothelialization [31]. The effect of CD8+ T cells on reduced neointima formation after arterial injury was attributed in part to increased function of the CD28high phenotype.…”

“…These changes were absent in sham sampling procedures and were not observed in other cell populations. Identification of possible CD8 T cell interactions with injured vascular wall, while novel in humans, is in line with studies showing the importance of CD8+T cells in the vascular injury response in mice [30, 31]. Interestingly, CD8 knockout increased neointimal formation and TNF levels in injured arteries and was also associated with delayed re-endothelialization [31].…”

Curcumin accelerates reendothelialization and ameliorates intimal hyperplasia in balloon-injured rat carotid artery via the upregulation of endothelial cell autophagy

“…The vessel tissue processing method was conducted and the degree of neointima formation was evaluated by measuring the luminal cross-sectional areas ( 23 , 24 ).…”

CD4+ lymphocytes improve venous blood flow in experimental arteriovenous fistulae

“…Research indicates that T cells are associated with exacerbation of atherosclerotic lesions, 19-21 while showing a protective effect against NIH after arterial injury. 22, 23 Interestingly, in the setting of arterial injury, further characterization revealed that this protective effect was mediated by CD8 + cells, 24-26 while their CD4 + counterparts in fact promoted neointima development. 27 …”