Lin Qiu-Yue, Bai Jie, Zhang Yun-Long, Li Hui-Hua
Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (Q.-Y.L., J.B., H.-H.L.).
Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China (Y.-L.Z., H.-H.L.).
Hypertension. 2023 Jan;80(1):57-69. doi: 10.1161/HYPERTENSIONAHA.122.20328. Epub 2022 Nov 15.
Leukocyte adhesion to endothelium is an early inflammatory response and is mainly controlled by the β2-integrins. However, the role of integrin CD11b/CD18 in the pathogenesis of hypertension and vascular dysfunction is unclear.
Hypertension was established by angiotensin II (490 ng/kg·per min) or deoxycorticosterone acetate salt. Hypertensive responses were studied in CD11b-deficient (CD11b) mice, bone marrow transplanted and wild-type (WT) mice that were administered anti-CD11b neutralizing antibody or agonist leukadherin-1. Blood pressure was monitored with tail-cuff method and radiotelemetry. Blood and vascular inflammatory cells were assessed by flow cytometry. Aortic remodeling and function were examined using histology and aortic ring analysis. Cell adhesion and migration were evaluated in vitro. The relationship between circulating CD11b immune cells and hypertension was analyzed in patients with hypertension.
We found that CD11b and CD18 expression as well as the CD45CD11bCD18 myeloid cells were highly increased in the aorta of angiotensin II-infused mice. Ablation or pharmacological inhibition of CD11b in mice significantly alleviated hypertension, aortic remodeling, superoxide generation, vascular dysfunction, and the infiltration of CD11b macrophages through reducing macrophage adhesion and migration. These effects were confirmed in WT mice reconstituted with CD11b-deficient bone marrow cells. Conversely, angiotensin II-induced hypertensive response was exacerbated by CD11b agonist leukadherin-1. Notably, circulating CD45CD11bCD18 myeloid cells and the ligand levels in hypertensive patients were significantly higher than in normotensive controls.
We demonstrated a critical significance of CD11b myeloid cells in hypertension and vascular dysfunction. Targeting CD11b may represent a novel therapeutic option for hypertension.
白细胞与内皮细胞的黏附是一种早期炎症反应，主要受β2整合素控制。然而，整合素CD11b/CD18在高血压发病机制和血管功能障碍中的作用尚不清楚。
通过输注血管紧张素II（490 ng/kg·每分钟）或醋酸脱氧皮质酮盐建立高血压模型。在缺乏CD11b（CD11b-/-）的小鼠、接受骨髓移植的小鼠以及给予抗CD11b中和抗体或激动剂白细胞黏附素-1的野生型（WT）小鼠中研究高血压反应。采用尾套法和无线电遥测技术监测血压。通过流式细胞术评估血液和血管炎症细胞。使用组织学和主动脉环分析检查主动脉重塑和功能。在体外评估细胞黏附和迁移。分析高血压患者循环CD11b免疫细胞与高血压之间的关系。
我们发现，在输注血管紧张素II的小鼠主动脉中，CD11b和CD18的表达以及CD45⁺CD11b⁺CD18⁺髓样细胞显著增加。在小鼠中消除或药理学抑制CD11b可通过减少巨噬细胞黏附和迁移，显著减轻高血压、主动脉重塑、超氧化物生成、血管功能障碍以及CD11b⁺巨噬细胞的浸润。在用缺乏CD11b的骨髓细胞重建的WT小鼠中证实了这些作用。相反，CD11b激动剂白细胞黏附素-1加剧了血管紧张素II诱导的高血压反应。值得注意的是，高血压患者循环CD45⁺CD11b⁺CD18⁺髓样细胞及其配体水平显著高于血压正常的对照组。
我们证明了CD11b⁺髓样细胞在高血压和血管功能障碍中的关键意义。靶向CD11b可能代表一种治疗高血压的新选择。
