Reskiawan A Kadir Rais, Alwjwaj Mansour, Ahmad Othman Othman, Rakkar Kamini, Sprigg Nikola, Bath Philip M, Bayraktutan Ulvi
Stroke, Academic Unit of Mental Health and Clinical Neuroscience, The University of Nottingham, United Kingdom.
Stroke, Academic Unit of Mental Health and Clinical Neuroscience, The University of Nottingham, United Kingdom.
Brain Res. 2022 Jul 15;1787:147925. doi: 10.1016/j.brainres.2022.147925. Epub 2022 Apr 22.
Ageing is characterised by a progressive loss of vascular endothelial function and integrity. Endothelial progenitor cells (EPCs) play an integral role in endothelial regeneration but are prone to age-dependent changes which may accelerate their senescence and diminish their availability and functionality. Considering these, we firstly investigated the quantity of circulating EPCs in older (73.3 ± 7.2 years) and younger (40.2 ± 14.3 years) healthy volunteers and showed sharp declines in the number of EPCs expressing stemness markers (CD34 + and/or CD133 + ) in older people. These coincided with the decreases in total anti-oxidant capacity (TAC) and concomitant increases in plasma levels of pro-inflammatory cytokine, TNF-α and anti-angiogenic factor, endostatin and thrombospondin-1. The subsequent experimental studies to scrutinise the effect of ageing on molecular and functional properties of outgrowth endothelial cells (OECs), the functional subtype of EPCs, showed that chronological ageing, mimicked by replicative senescence, profoundly impaired proliferation, migration, tubulogenesis, and blood-brain barrier (BBB)-forming capacity of these cells. Similar to those seen in the clinical observational studies, senescent OECs also manifested decreased TAC and increased pro-oxidant NADPH oxidase activity and endostatin level. Suppressing oxidative stress level using structurally and functionally distinct anti-oxidants, namely vitamin C or VAS2870, an NADPH oxidase inhibitor, delayed OEC senescence and restored their tubulogenic and BBB-forming capacities. In conclusion, the enhanced oxidative stress level that develops during physiological ageing may promote EPC senescence and evoke endothelial dysfunction. Effective control of oxidative stress using either compound somewhat delays both phenomena and augments EPC functionality.
衰老的特征是血管内皮功能和完整性的逐渐丧失。内皮祖细胞（EPCs）在内皮再生中发挥着不可或缺的作用，但容易发生与年龄相关的变化，这可能会加速其衰老，并降低其可用性和功能。考虑到这些，我们首先调查了老年（73.3±7.2岁）和年轻（40.2±14.3岁）健康志愿者循环EPCs的数量，结果显示老年人中表达干性标志物（CD34 +和/或CD133 +）的EPCs数量急剧下降。这些变化与总抗氧化能力（TAC）的降低以及促炎细胞因子TNF-α、抗血管生成因子内皮抑素和血小板反应蛋白-1血浆水平的相应升高相一致。随后的实验研究旨在仔细研究衰老对EPCs功能亚型——迁出内皮细胞（OECs）分子和功能特性的影响，结果表明，由复制性衰老模拟的自然衰老严重损害了这些细胞的增殖、迁移、成管和血脑屏障（BBB）形成能力。与临床观察研究中所见相似，衰老的OECs也表现出TAC降低、促氧化剂NADPH氧化酶活性增加和内皮抑素水平升高。使用结构和功能不同的抗氧化剂（即维生素C或NADPH氧化酶抑制剂VAS2870）抑制氧化应激水平，可延缓OEC衰老，并恢复其成管和BBB形成能力。总之，生理衰老过程中产生的氧化应激水平升高可能会促进EPC衰老并引发内皮功能障碍。使用任何一种化合物有效控制氧化应激可在一定程度上延缓这两种现象，并增强EPC功能。
