Aging increases risk for ischemic vascular diseases. Bone marrow–derived hematopoietic stem/progenitor cells (HSPCs) are known to stimulate vascular regeneration. Activation of either the Mas receptor (MasR) by angiotensin-(1-7) (Ang-(1-7)) or angiotensin-converting enzyme-2 (ACE2) stimulates vasoreparative functions in HSPCs. This study tested if aging is associated with decreased ACE2 expression in HSPCs and if Ang-(1-7) restores vasoreparative functions. Flow cytometric enumeration of Lin⁻CD45^lowCD34⁺ cells was carried out in peripheral blood of male or female individuals (22–83 years of age). Activity of ACE2 or the classical angiotensin-converting enzyme (ACE) was determined in lysates of HSPCs. Lin⁻Sca-1⁺cKit⁺ (LSK) cells were isolated from young (3–5 months) or old (20–22 months) mice, and migration and proliferation were evaluated. Old mice were treated with Ang-(1-7), and mobilization of HSPCs was determined following ischemia induced by femoral ligation. A laser Doppler blood flow meter was used to determine blood flow. Aging was associated with decreased number (Spearman r = − 0.598, P < 0.0001, n = 56), decreased ACE2 (r = − 0.677, P < 0.0004), and increased ACE activity (r = 0.872, P < 0.0001) (n = 23) in HSPCs. Migration or proliferation of LSK cells in basal or in response to stromal-derived factor-1α in old cells is attenuated compared to young, and these dysfunctions were reversed by Ang-(1-7). Ischemia increased the number of circulating LSK cells in young mice, and blood flow to ischemic areas was recovered. These responses were impaired in old mice but were restored by treatment with Ang-(1-7). These results suggest that activation of ACE2 or MasR would be a promising approach for enhancing ischemic vascular repair in aging.

衰老会增加缺血性血管疾病的风险。众所周知，骨髓来源的造血干/祖细胞 (HSPC) 可刺激血管再生。血管紧张素-(1-7) (Ang-(1-7)) 或血管紧张素转换酶-2 (ACE2) 激活 Mas 受体 (MasR) 可刺激 HSPC 的血管修复功能。这项研究测试了衰老是否与 HSPC 中 ACE2 表达降低有关，以及 Ang-(1-7) 是否恢复血管修复功能。在男性或女性个体（22-83 岁）的外周血中进行Lin ^- CD45^低CD34 ⁺细胞的流式细胞计数。ACE2 或经典血管紧张素转换酶 (ACE) 的活性在 HSPC 的裂解物中测定。林^- Sca-1 ⁺从年轻（3-5 个月）或老年（20-22 个月）小鼠中分离出cKit ⁺ (LSK) 细胞，并评估迁移和增殖。用 Ang-(1-7) 治疗老年小鼠，并在股骨结扎诱导缺血后测定 HSPCs 的动员。使用激光多普勒血流仪测定血流。衰老与数量减少（Spearman r  = - 0.598，P  < 0.0001，n  = 56）、ACE2 减少（r  = - 0.677，P  < 0.0004）和 ACE 活性增加（r  = 0.872，P  < 0.0001）（n = 23) 在 HSPC 中。与年轻细胞相比，LSK 细胞在基底细胞或对基质衍生因子 1α 的反应中的迁移或增殖比年轻细胞减弱，并且这些功能障碍被 Ang-(1-7) 逆转。缺血增加了年轻小鼠循环 LSK 细胞的数量，并且恢复了流向缺血区域的血流。这些反应在老年小鼠中受损，但通过用 Ang-(1-7) 治疗恢复。这些结果表明，激活 ACE2 或 MasR 将是增强衰老中缺血性血管修复的有前景的方法。