Mitochondrial dysfunction-mediated decline in angiogenic capacity of endothelial progenitor cells is associated with capillary rarefaction in patients with hypertension via downregulation of CXCR4/JAK2/SIRT5 signaling
Mitochondrial dysfunction-mediated decline in angiogenic capacity of endothelial progenitor cells is associated with capillary rarefaction in patients with hypertension via downregulation of CXCR4/JAK2/SIRT5 signaling
复制标题
线粒体功能障碍介导的内皮祖细胞血管生成能力下降与高血压患者毛细血管稀疏相关，通过下调 CXCR4/JAK2/SIRT5 信号传导
DOI：
10.1016/j.ebiom.2019.03.031
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发表时间：
2019
期刊：
影响因子：
11.1
通讯作者：
陶军
中科院分区：
文献类型：
--
作者：
夏文豪;余冰波;支慧;张小宇;梁建文;何江;苏晨;张高星;陶军
背景：高血压患者出现毛细血管密度和内皮祖细胞的减少，但高血压患者的毛细血管疏松是否与内皮祖细胞的血管生成缺陷有关尚不清楚。我们假设高血压患者晚期内皮祖细胞线粒体功能受损与CXCR4/JAK2/SIRT5信号通路缺陷导致的毛细血管微循环结构缺失有关。检测循环内皮祖细胞的血管生成能力和线粒体功能。结果：高血压患者甲皱和眼底毛细血管密度显著降低，与体外晚期EPC功能和体内血管生成能力降低相平行。同时，高血压时EPC功能下降伴随线粒体超微结构受损，线粒体膜电位降低，耗氧量减少，ROS生成增加，NADH水平升高。鱼藤酮可抑制EPC的耗氧率、过量ROS的产生和基质金属蛋白酶的丢失，从而显著降低EPC的体外功能。此外，高血压患者内皮祖细胞SIRT5的表达明显降低，这与线粒体功能障碍有关。CXCR4基因转移增强了SIRT5的表达，改善了线粒体功能，增强了血管生成能力。SIRT5上调对晚期EPC介导的血管生成的有利影响可以通过阻断CXCR4/JAK2/SIRT5信号通路而取消。解释：线粒体功能障碍介导的血管生成能力下降是由于CXCR4/JAK2/缺陷。晚期EPC的SIRT5信号可能是高血压毛细血管稀疏的原因。我们的发现为EPC线粒体作为治疗高血压相关微血管密度丧失的新靶点的潜力提供了洞察力。
Background: Hypertensive patients exhibit decline in capillary density and endothelial progenitor cells (EPCs)..However, whether capillary rarefaction in hypertension is associated with defect angiogenesis of EPCs remains.unknown. We hypothesized that impaired mitochondrial function of late EPCs in hypertension is associated.with the structural lack of capillary microcirculation via deficient CXCR4/JAK2/SIRT5 signaling..Methods: We performed capillary microcirculation detection in hypertensive patients and healthy subjects. Angiogenic.capacity and mitochondrial function of circulating EPCs were evaluated. The underlying mechanisms.were further investigated by genetic inhibition and overexpression..Findings: Capillary density of nail fold and eye fundus were significantly reduced in hypertensive patients, which.was paralleled to decreased in vitro late EPC function and in vivo angiogenic capacity. Meanwhile the decline of.EPC function in hypertensionwas accompanied by impaired mitochondrial ultrastructure, diminished mitochondrial.membrane potential, reduced oxygen consumption, increased ROS generation and NADH level. Rotenone.induced inhibition of oxygen consumption rate, excessive ROS generation and loss ofMMP, which markedly decreased.the in vitro functions of EPCs. Furthermore, SIRT5 expression of EPCs in hypertension was markedly reduced,.which was correlated to mitochondrial dysfunction. CXCR4 gene transfer enhanced SIRT5 expression,.improved mitochondrial functions and augmented angiogenic capacity of EPCs. The beneficial impacts of SIRT5.up-regulation on late EPC-mediated angiogenesis can be abrogated by blockade of CXCR4/JAK2/SIRT5 signaling.pathway..Interpretation: Mitochondrial dysfunction-mediated fall in angiogenic capacity due to deficient CXCR4/JAK2/.SIRT5 signaling of late EPCs is probably responsible for the capillary rarefaction in hypertension. Our findings provide.insight into the potential of EPC mitochondria as a novel target for the treatment of hypertension-related.loss of microvascular density.