Abstract | 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 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. INTERPRETATION: FUNDS: National Nature Science Foundation of China, 973Program, the Nature Science Foundation of Guangdong.
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Authors | Bing-Bo Yu, Hui Zhi, Xiao-Yu Zhang, Jian-Wen Liang, Jiang He, Chen Su, Wen-Hao Xia, Gao-Xing Zhang, Jun Tao |
Journal | EBioMedicine
(EBioMedicine)
Vol. 42
Pg. 64-75
(Apr 2019)
ISSN: 2352-3964 [Electronic] Netherlands |
PMID | 30904607
(Publication Type: Journal Article)
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Copyright | Copyright © 2019. Published by Elsevier B.V. |
Chemical References |
- Biomarkers
- CXCR4 protein, human
- Reactive Oxygen Species
- Receptors, CXCR4
- JAK2 protein, human
- Janus Kinase 2
- SIRT5 protein, human
- Sirtuins
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Topics |
- Animals
- Biomarkers
- Disease Models, Animal
- Endothelial Progenitor Cells
(cytology, metabolism)
- Gene Expression
- Humans
- Hypertension
(etiology, metabolism, pathology)
- Janus Kinase 2
(genetics, metabolism)
- Male
- Membrane Potential, Mitochondrial
- Mice
- Microvascular Rarefaction
(diagnostic imaging, genetics, metabolism)
- Mitochondria
(genetics, metabolism, ultrastructure)
- Models, Biological
- Neovascularization, Physiologic
(genetics)
- Oxygen Consumption
- Rats
- Rats, Inbred SHR
- Reactive Oxygen Species
(metabolism)
- Receptors, CXCR4
(genetics, metabolism)
- Risk Factors
- Signal Transduction
- Sirtuins
(genetics, metabolism)
- Stem Cell Transplantation
- Transduction, Genetic
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