Dysfunction of late endothelial progenitor cells (EPCs) has been suggested to be associated with hypertension. β2 adrenergic receptor (β2AR) is a novel and key target for EPCs homing. Here, we proposed that attenuated β2AR signaling contributes to EPCs dysfunction, whereas enhanced β2AR signaling restores EPCs' functions in hypertension. EPCs derived from hypertensive patients exhibited reduced cell number, impaired in vitro migratory and adhesion abilities, and impaired re-endothelialization after transplantation in nude mice with carotid artery injury. β2AR expression of EPCs from hypertensive patients was markedly downregulated, whereas the phosphorylation of the p38 mitogen-activated protein kinase (p38-MAPK) was elevated. The cleaved caspase-3 levels were elevated in EPCs. The overexpression of β2AR in EPCs from hypertensive patients inhibited p38-MAPK signaling while enhanced in vitro EPC proliferation, migration and adhesion, and in vivo re-endothelialization. The β2AR-mediated effects were attenuated by treating the EPCs with a neutralizing monoclonal antibody against β2AR, which could be partially antagonized by the p38-MAPK inhibitor SB203580. Moreover, shear stress stimulation, a classic non-pharmacological intervention, increased the phosphorylation levels of β2AR and enhanced the in vitro and in vivo functions of EPCs from hypertensive patients. Collectively, the current investigation demonstrated that impaired β2AR/p38MAPK/caspase-3 signaling at least partially reduced the re-endothelialization capacity of EPCs from hypertensive patients. Restoration of β2AR expression and shear stress treatment could improve their endothelial repair capacity by regulating the p38MAPK/caspase-3 signaling pathway. The clinical significance of β2AR in endothelium repair still requires further investigation.

中文翻译：

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β2AR升高对高血压患者晚期内皮祖细胞介导的再内皮化能力的重要性

晚期内皮祖细胞（EPC）的功能障碍已被认为与高血压有关。β2肾上腺素能受体（β2AR）是EPC归巢的一种新型关键靶标。在这里，我们提出减弱的β2AR信号传导可导致EPC功能障碍，而增强的β2AR信号可恢复EPC在高血压中的功能。在患有颈动脉损伤的裸鼠移植后，源自高血压患者的EPC表现出减少的细胞数量，受损的体外迁移和粘附能力以及受损的再内皮化。高血压患者EPC的β2AR表达明显下调，而p38丝裂原活化蛋白激酶（p38-MAPK）的磷酸化升高。在EPC中，裂解的caspase-3水平升高。高血压患者EPC中β2AR的过度表达抑制p38-MAPK信号传导，同时增强体外EPC增殖，迁移和粘附以及体内再内皮化。通过用抗β2AR的中和性单克隆抗体处理EPC，可以减弱β2AR介导的作用，该抗体可以被p38-MAPK抑制剂SB203580部分拮抗。此外，剪切应力刺激是一种经典的非药物干预措施，可增加β2AR的磷酸化水平，并增强高血压患者EPC的体外和体内功能。总的来说，当前的研究表明，受损的β2AR/ p38MAPK / caspase-3信号传导至少部分降低了高血压患者EPC的再内皮化能力。β2AR表达的恢复和切应力处理可以通过调节p38MAPK / caspase-3信号通路来提高其内皮修复能力。β2AR在内皮修复中的临床意义尚需进一步研究。