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

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.

Sitagliptin ameliorates renal tubular injury in diabetic kidney disease via STAT3‐dependent mitochondrial homeostasis through SDF‐1α/CXCR4 pathway

“…A recent study from Tao‐Jun's group indicated that CXCR4 could maintain MMP and mitochondrial function through the JAK2‐dependent pathway, 27 possibly via activating downstream STAT3. It is well known that STAT3 serves mainly as a transcription factor that translocate into the nucleus upon phosphorylation, and it is thought that STAT3 activation mediates the pathogenesis of DKD 58 .…”

Mitophagy in Cardiovascular Diseases

“…EPCs in HT patients present mitochondrial dysfunctions linked to impairment of the CXCR4/JAK2/SIRT5 signaling pathway and failure of angiogenic capacity. [70] Arrhythmia Decrease in mitophagy leads to pro-arrhythmic spontaneous Ca 2+ release via oxidized RyR2s by mito-ROS. [71] Peripheral vascular disease PVD fibers present an accumulation of LC3 that is not completely colocalized with LAMP2.…”

“…In addition to defects in this mitochondrial quality control system, general organelle dysfunction has been reported to be involved during HT [70,152,153]. At the level of the microvasculature of HT patients, capillary rarefaction is an important clinical sign to be evaluated.…”

“…Capillary rarefaction may be counteracted by the action of endothelial progenitor cells (EPCs) strongly involved in angiogenesis, but mitochondrial dysfunction in these cells leads to a significant imbalance between microvasculature resistance and new vessel formation. Downregulation of the C-X-C motif chemokine receptor 4 (CXCR4)/Janus kinase 2 (JAK2)/sirtuin 5 (SIRT5) signaling pathway is responsible for EPC dysfunction exacerbating HT in patients; indeed, CXCR4, which is depleted in HT samples, is able to improve SIRT5-dependent mitochondrial function via JAK2 phosphorylation [70] (Table 1).…”

Epigenetic Control of Mitochondrial Function in the Vasculature

“…SIRT5, a weak deacetylase with strong desuccinylase, demalonylase, and deglutarylase activity, has been also implicated in regulating different aspects of mitochondrial metabolism and cardiovascular function (140). SIRT5 downregulation was recently associated with mitochondrial dysfunction in endothelial progenitor cells of patients with arterial hypertension (141). Other studies reported that SIRT5 deficiency exert a protective role by suppressing mitochondrial ATP production and promoting AMPK activation in response to energy stress.…”