Chen Minghong, Chen Junyu, Liu Yu, Wang Xuerui, Yao Meilian, Chen Jing, Zhang Jian, Huang Qun
Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Center of Coronary Circulation, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Aging Cell. 2025 Jul;24(7):e70059. doi: 10.1111/acel.70059. Epub 2025 Apr 17.
Peripheral arterial disease is a common vascular disease in the elderly. Therapeutic revascularization, including angiogenic and arteriogenic therapy, is a promising treatment approach for peripheral arterial disease. However, the progress of clinical trials is not ideal, possibly due to insufficiency of preclinical models, such as not taking into account the effect of aging on vascular regeneration. Macrophages are crucial in angiogenesis and arteriogenesis. The aging microenvironment typically makes recruited monocytes and macrophages more susceptible to senescence. However, the feature of macrophages in ischemic hindlimb muscle of old individuals and their underlying role remains unclear. In this study, we reveal that macrophages of ischemic skeletal muscle in old mice are more senescent and proinflammatory. By transplanting macrophages into mice following hindlimb ischemia, we find senescent macrophages inhibit revascularization. Mechanistically, these senescent macrophages induce endothelial dysfunction via increasing vascular endothelial growth factor A-165B (VEGF-A165B) expression and secretion, and eventually impair revascularization. Notably, plasma VEGF-A165B levels are elevated in old patients with PAD and positively associated with a lower ankle brachial index (ABI). Our study suggests that targeting the senescent macrophages presents an avenue to improve age-related revascularization damage.
外周动脉疾病是老年人常见的血管疾病。包括血管生成和动脉生成治疗在内的治疗性血管重建是外周动脉疾病一种有前景的治疗方法。然而，临床试验进展并不理想，这可能是由于临床前模型的不足，比如未考虑衰老对血管再生的影响。巨噬细胞在血管生成和动脉生成中起关键作用。衰老的微环境通常使募集的单核细胞和巨噬细胞更容易衰老。然而，老年个体缺血后肢肌肉中巨噬细胞的特征及其潜在作用仍不清楚。在本研究中，我们发现老年小鼠缺血骨骼肌中的巨噬细胞更衰老且具有促炎作用。通过在小鼠后肢缺血后移植巨噬细胞，我们发现衰老的巨噬细胞会抑制血管重建。从机制上来说，这些衰老的巨噬细胞通过增加血管内皮生长因子A-165B（VEGF-A165B）的表达和分泌来诱导内皮功能障碍，并最终损害血管重建。值得注意的是，外周动脉疾病老年患者血浆VEGF-A165B水平升高，且与较低的踝臂指数（ABI）呈正相关。我们的研究表明，针对衰老的巨噬细胞是改善与年龄相关的血管重建损伤的一条途径。
