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
Authors: Jian-Wen Liang
Bing-Bo Yu
Jun Tao
Gao-Xing Zhang
Chen Su
Wen-Hao Xia
Hui Zhi
Xiao-Yu Zhang
Jiang He
Journal: EBioMedicine (2019)
Discipline: CLINICAL MEDICINE
Keywords: Angiogenesis; CXCR4; EPCs; Hypertension; Microcirculation
Affiliations: 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. Electronic address: ., 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. Electronic address: .

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: 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. Funds: National Nature Science Foundation of China, 973Program, the Nature Science Foundation of Guangdong. 

Retracted: No

PubPeer comments:
 In Figure 1d, two photograps of a mouse are surprisingly similar, despite they are taken at day 7 and day 14. The blood flow after injection of EPC is different, but the mouse seems to have been  frozen between the photo shots. ![file] , 
 Thank you very much for your valuable comment. We appreciate your interest in our work and your efforts to ensure the accuracy of scientific records and the integrity of scientific research. These are also extremely important and helpful to us. According to your question, we took immediate action to investigate the problem you raised and rechecked our manuscripts carefully. Exactly, we put a wrong representative photograph of 14 days hindlimb ischemia because all of a miceu2019s photographs were in the same file. We regret our failure to detect this mistake at the time of proof checking and apologize for any negligence in our work and any inconvenience. More recently, one paper (Cells 2020, 9, 50; doi:10.3390 cells9010050) also has highlighted potential therapeutic targets to improve microvasular dysfunction in hypertention which support our work. The unintentional mistake will be reported to the journal for their taking appropriate step for further correction. In fact, it is a valuable learning opportunity for us and we will pay more attention to the accuracy in the future. Thank you very much for your rigorous academic attitude and pertinent suggestion. ,