Abstract
Objective
: This study aims to determine the mechanisms by which aging prolongs inflammation in response to vascular injury, and exaggerate neointimal formation.
Methods and Results
: Using balloon injury model in rat iliac arteries, we found that aging rats (22 month-old) developed thicker neointima at 4 weeks after injury than their younger counter parts (4 month-old) (I/M: 0.8 ± 0.2 vs. 0.54 ± 0.15, p<0.008). We also found that injured arteries in aging animals accumulated more alpha-actin positive VSMC in the neointima than those from the young ones (500 ± 100 vs. 320 ± 120 cell/mm
2
). Although similar number of macrophages (CD68+; detected by immunohistochemistry; IHC) appeared in the adventitia 24 h after injury in both groups, these cells disappeared in the young arteries after 3 days, while remained in the media and neointima of aging arteries until 30 days after injury. Macrophages in aging arteries were CD163 negative and IL-6 and IL-18 positive, indicating they are of pro-inflammatory phenotype. There were no differences in the number of vascular T cells and dendritic cells between groups. Vascular apoptotic cells were determined by ISOL combined with IHC either for VSMC or macrophages. Aging arteries had fewer apoptotic VSMC or macrophages (0.2% ± 0.05) at any time after vascular injury when compared with the younger ones which had abundant vascular apoptotic cells in the media and neointima at 7 days after surgery (2.7% ± 0.45). Finally, the vascular cytokines production was assessed after balloon injury using the LincoPlex system. At three days after injury aging arteries contained three folds or higher levels of IL18, IL-6, Gro KC, and Leptin than the young ones. These pro-inflammatory cytokines stayed elevated in the aging vessels for most of the arterial remodeling process. In contrast, when compared with aging arteries, young arteries produced three times or higher levels of anti-inflammatory cytokines IL-10, IL-17, IL13 and IL-9 at seven days after injury.
Conclusions
: Our data suggests that aging inhibits the apoptotic resolution of the vascular inflammatory response to injury, leading to exaggerated neointimal formation.