Department of Surgery and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida;
Am J Physiol Heart Circ Physiol. 2014 Mar 1;306(5):H641-53. doi: 10.1152/ajpheart.00641.2013. Epub 2014 Jan 10.
Aging has been associated with pathological vascular remodeling and increased neointimal hyperplasia. The understanding of how aging exacerbates this process is fundamental to prevent cardiovascular complications in the elderly. This study proposes a mechanism by which aging sustains leukocyte adhesion, vascular inflammation, and increased neointimal thickness after injury. The effect of aging on vascular remodeling was assessed in the rat balloon injury model using microarray analysis, immunohistochemistry, and LINCOplex assays. The injured arteries in aging rats developed thicker neointimas than those in younger animals, and this significantly correlated with a higher number of tissue macrophages and increased vascular IL-18. Indeed, IL-18 was 23-fold more abundant in the injured vasculature of aged animals compared with young rats, while circulating levels were similar in both groups of animals. The depletion of macrophages in aged rats with clodronate liposomes ameliorated vascular accumulation of IL-18 and significantly decreased neointimal formation. IL-18 was found to inhibit apoptosis of vascular smooth muscle cells (VSMC) and macrophages, thus favoring both the formation and inflammation of the neointima. In addition, injured arteries of aged rats accumulated 18-fold more fibrinogen-γ than those of young animals. Incubation of rat peritoneal macrophages with immobilized IL-18 increased leukocyte adhesion to fibrinogen and suggested a proinflammatory positive feedback loop among macrophages, VSMC, and the deposition of fibrinogen during neointimal hyperplasia. In conclusion, our data reveal that concentration changes in vascular cytokine and fibrinogen following injury in aging rats contribute to local inflammation and postinjury neointima formation.
衰老是与病理性血管重塑和新生内膜过度增生有关的。了解衰老如何加剧这一过程，对于预防老年人的心血管并发症至关重要。本研究提出了一个机制，即衰老如何维持白细胞黏附、血管炎症和损伤后新生内膜厚度的增加。使用微阵列分析、免疫组织化学和 LINCOplex 测定法，评估了衰老对大鼠球囊损伤模型中血管重塑的影响。结果显示，与年轻动物相比，衰老大鼠的损伤动脉形成了更厚的新生内膜，这与组织巨噬细胞数量增加和血管白介素-18（IL-18）增加显著相关。事实上，与年轻大鼠相比，衰老动物损伤血管中 IL-18 的含量增加了 23 倍，而两组动物的循环水平相似。用氯膦酸盐脂质体耗竭衰老大鼠的巨噬细胞，可改善血管中 IL-18 的积累，并显著减少新生内膜的形成。IL-18 被发现抑制血管平滑肌细胞（VSMC）和巨噬细胞的凋亡，从而有利于新生内膜的形成和炎症。此外，与年轻动物相比，衰老大鼠损伤的动脉中纤维蛋白原-γ 的积累增加了 18 倍。将固定化 IL-18 孵育大鼠腹腔巨噬细胞，增加了白细胞对纤维蛋白原的黏附，这表明在新生内膜过度增生过程中，巨噬细胞、VSMC 和纤维蛋白原的沉积之间存在一种促炎的正反馈循环。总之，我们的数据揭示了衰老大鼠损伤后血管细胞因子和纤维蛋白原浓度的变化，导致局部炎症和损伤后新生内膜形成。
