BMP4/Id2 signaling pathway is a novel therapeutic target for late outgrowth endothelial progenitor cell-mediated endothelial injury repair
BMP4/Id2 signaling pathway is a novel therapeutic target for late outgrowth endothelial progenitor cell-mediated endothelial injury repair
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BMP4/Id2信号通路是晚期生长内皮祖细胞介导的内皮损伤修复的新治疗靶点。
DOI：
10.1016/j.ijcard.2016.11.027
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发表时间：
2017-02-01
影响因子：
3.5
通讯作者：
Tao, Jun
中科院分区：
文献类型：
--
作者：
Xia, Wen-Hao;Chen, Long;Tao, Jun
背景资料：内皮祖细胞（Endothelial progenitor cells，EPCs）在动脉损伤后的内皮修复中起着关键作用，但晚期生长的EPCs（late outgrowth EPCs，LEPCs）在内皮修复中的分子机制仍有待进一步研究。骨形态发生蛋白4（BMP 4）参与血管损伤介导的LEPC动员和归巢。在此，我们研究了BMP 4修饰的信号通路在人LEPC相关内皮修复中的影响及其分子机制。方法和结果：体外培养28天后，用不同浓度的重组BMP 4预处理人LEPC（0、10、50或100 ng/mL），在体外能显著增强人LEPCs的迁移和粘附能力，在体内能显著加速人LEPCs的内皮修复能力移植到颈动脉剥脱损伤的裸鼠体内。此外，主要的Id基因（Id 2），一个良好的特征化的下游目标的BMP 4，上调与重组BMP 4孵育的LEPCs。BMP-4诱导的人LEPCs的体外功能活性和体内内皮修复能力的增强被BMP拮抗剂Noggin或shRNA介导的BMP-4表达的敲低预处理所消除。结论：本研究首次证实了BMP 4相关信号通路在人LEPCs内皮修复能力中的重要作用。上调人LEPCs中BMP 4修饰的信号通路可能是损伤后内皮修复的一种新的治疗策略。(C)由Elsevier爱尔兰Ltd.出版
Background: Endothelial progenitor cells (EPCs) play a pivotal role in endothelial repair following artery injury, however, the molecular mechanism of late outgrowth EPCs (LEPCs) in endothelial repair remained to be studied. Bone morphogenetic protein 4 (BMP4) is involved in vascular injury-mediated mobilization and homing of LEPCs. Here, we investigated the influence of BMP4-modified signaling pathway in LEPC-related endothelial repair of human and underlying molecular mechanism.Methods and results: In vitro, after a 28 day culture, human LEPCs were pretreated with different concentrations of recombinant BMP4 (0, 10, 50, or 100 ng/mL), which markedly augmented the migration and adhesion in vitro and demonstrated a significantly accelerated in vivo endothelial repair capacity of human LEPCs after transplantation into nude mice with carotid artery denudation injury. Moreover, the main Id gene (Id2), a well-characterized down-streaming target of BMP4, upregulated in LEPCs incubated with recombinant BMP4. The BMP4-induced enhancement in in vitro functional activities and in vivo endothelial repair capacity of human LEPCs were abolished by pretreatment with BMP antagonist Noggin or shRNA-mediated knockdown of BMP4 expression. Furthermore, BMP4 gene transfer remarkably activated BMP4-mediated signaling pathway and facilitated therapeutic endothelial repair capacity of LEPCs, and the improved functional activities of human LEPCs could be inhibited by Noggin.Conclusion: Thus, the present study demonstrates for the first time that BMP4-related signaling pathway is essential with endothelial repair capacity of LEPCs in human. The upregulation of BMP4-modified signaling pathway in human LEPCs may be a novel therapeutic strategy for endothelial repair after injury. (C) 2016 Published by Elsevier Ireland Ltd.