Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, China; NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, China.
Department of Cardiovascular Disease, The Jiangmen Central Hospital, China.
EBioMedicine. 2019 Apr;42:64-75. doi: 10.1016/j.ebiom.2019.03.031. Epub 2019 Mar 21.
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.
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.
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 hypertension was 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 of MMP, 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.
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.
National Nature Science Foundation of China, 973Program, the Nature Science Foundation of Guangdong.
高血压患者的毛细血管密度和内皮祖细胞（EPC）下降。然而，高血压中毛细血管稀疏是否与 EPC 血管生成缺陷有关尚不清楚。我们假设高血压中晚期 EPC 的线粒体功能受损与 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。
我们对高血压患者和健康受试者进行了毛细血管微循环检测。评估了循环 EPC 的血管生成能力和线粒体功能。通过基因抑制和过表达进一步研究了潜在机制。
高血压患者的甲襞和眼底毛细血管密度明显降低，这与体外晚期 EPC 功能和体内血管生成能力下降相平行。同时，高血压中 EPC 功能的下降伴随着线粒体超微结构受损、线粒体膜电位降低、耗氧量减少、ROS 生成增加和 NADH 水平升高。鱼藤酮诱导的耗氧量抑制、ROS 生成过多和 MMP 丧失，显著降低了 EPC 的体外功能。此外，高血压患者 EPC 的 SIRT5 表达明显减少，与线粒体功能障碍相关。CXCR4 基因转染增强了 SIRT5 表达，改善了线粒体功能，增强了 EPC 的血管生成能力。SIRT5 上调对晚期 EPC 介导的血管生成的有益影响可被阻断 CXCR4/JAK2/SIRT5 信号通路所抵消。
由于晚期 EPC 中 CXCR4/JAK2/SIRT5 信号的缺陷导致的线粒体功能障碍引起的血管生成能力下降可能是高血压中毛细血管稀疏的原因。我们的研究结果为 EPC 线粒体作为治疗高血压相关微血管密度丧失的新靶点提供了依据。
国家自然科学基金、973 计划、广东省自然科学基金。
