The TRPM7 channel reprograms cellular glycolysis to drive tumorigenesis and angiogenesis.

Cancer or endothelial cells preferably catabolize glucose through aerobic glycolysis rather than oxidative phosphorylation. Intracellular ionic signaling has been shown to regulate glucose metabolism, but the underlying ion channel has yet to be identified. RNA-seq, metabolomics and genetic assay revealed that the TRPM7 channel regulated cellular glycolysis. Deletion of TRPM7 suppressed cancer cell glycolysis and reduced the xenograft tumor burden. Deficiency of endothelial TRPM7 inhibited postnatal retinal angiogenesis in mice. Mechanistically, TRPM7 transcriptionally regulated the solute carrier family 2 member 3 (SLC2A3, also known as GLUT3) via Ca2+ influx-induced calcineurin activation. Furthermore, CREB-regulated transcription coactivator 2 (CRTC2) and CREB act downstream of calcineurin to relay Ca2+ signal to SLC2A3 transcription. Expression of the constitutively active CRTC2 or CREB in TRPM7 knockout cell normalized glycolytic metabolism and cell growth. The TRPM7 channel represents a novel regulator of glycolytic reprogramming. Inhibition of the TRPM7-dependent glycolysis could be harnessed for cancer therapy.

Prophylactic exercise-derived circulating exosomal miR-125a-5p promotes endogenous revascularization after hindlimb ischemia by targeting endothelin converting enzyme 1.

Background: Prophylactic exercise improves clinical outcomes in patients experiencing severe ischemic diseases. Previous studies have shown that exercise could alter the amount or content of circulating exosomes. However, little is known about the role of precursory exercise-derived circulating exosomes (Exe-Exo) in ischemic diseases. We therefore aimed to explore the function and mechanism of Exe-Exo in endogenous revascularization and perfusion recovery in peripheral arterial disease. Methods and Results: We first determined that 4 weeks of precursory treadmill exercise improved perfusion recovery on days 7, 14 and 21 after unilateral femoral artery ligation (FAL) but had no effect immediately after ligation. Then, local muscle delivery of Exe-Exo promotes arteriogenesis, angiogenesis and perfusion recovery, which could be abolished by GW4869, a well-recognized pharmacological agent inhibiting exosome release. This suggests that Exe-Exo mediated exercise-induced revascularization. In vitro, Exe-Exo enhanced endothelial cell proliferation, migration and tube formation. In addition, we identified miR-125a-5p as a novel exerkine through exosomal miRNA sequencing and RT-qPCR validation. Inhibition of miR-125a-5p abrogated the beneficial effects of Exe-Exo both in vivo and in vitro. Mechanistically, these exercise-afforded benefits were attributed to the exosomal miR-125a-5p downregulation of ECE1 expression and the subsequent activation of the AKT/eNOS downstream signaling pathway. Specifically, skeletal muscle may be a major tissue source of exercise-induced exosomal miR-125a-5p via fluorescence in situ hybridization. Conclusions: Endogenous circulating exosomal miR-125a-5p promotes exercise-induced revascularization via targeting ECE1 and activating AKT/eNOS downstream signaling pathway. Identify exosomal miR-125a-5p as a novel exerkine, and highlight its potential therapeutic role in the prevention and treatment of peripheral arterial disease.

Single-cell profiling of vascular endothelial cells reveals progressive organ-specific vulnerabilities during obesity.

Obesity promotes diverse pathologies, including atherosclerosis and dementia, which frequently involve vascular defects and endothelial cell (EC) dysfunction. Each organ has distinct EC subtypes, but whether ECs are differentially affected by obesity is unknown. Here we use single-cell RNA sequencing to analyze transcriptomes of ~375,000 ECs from seven organs in male mice at progressive stages of obesity to identify organ-specific vulnerabilities. We find that obesity deregulates gene expression networks, including lipid handling, metabolic pathways and AP1 transcription factor and inflammatory signaling, in an organ- and EC-subtype-specific manner. The transcriptomic aberrations worsen with sustained obesity and are only partially mitigated by dietary intervention and weight loss. For example, dietary intervention substantially attenuates dysregulation of liver, but not kidney, EC transcriptomes. Through integration with human genome-wide association study data, we further identify a subset of vascular disease risk genes that are induced by obesity. Our work catalogs the impact of obesity on the endothelium, constitutes a useful resource and reveals leads for investigation as potential therapeutic targets.

Association of statins with mortality in type 2 diabetes patients with intensive glycemic therapy.

AIMS: Intensive glycemic therapy could lead to increased mortality in patients with type 2 diabetes mellitus (T2DM). But it remains unclear whether statins use improves prognosis in T2DM patients with intensive glycemic therapy. METHODS: Using data from Action to Control Cardiovascular Risk in Diabetes trial and performing propensity score matching and Cox proportional hazards regression, we explored the relationship between statin use and the risk of mortality in intensive-therapy group. RESULTS: In the intensive-therapy group, total mortality (TM) in patients with statins treatment is lower than those without statins (hazard ratio (HR), 0.68; 95% confidence interval (CI) 0.49-0.95; P = 0.022); the effects of statins on cardiovascular mortality (CM) and primary outcomes (PO), however, were negligible (CM: HR 0.96; 95% CI 0.61-1.51; P = 0.854; PO: HR 0.88; 95% CI 0.65-1.19; P = 0.415). Besides, the risk of TM, CM and PO in patients with the intensive therapy combined with statins use was similar to those in the standard group (TM: P = 0.445; CM: P = 0.362; PO: P = 0.637). CONCLUSIONS: Statins may alleviate the risk of TM in T2DM patients receiving intensive glycemic therapy.

Image quality and diagnostic accuracy of a handheld nonmydriatic fundus camera: Feasibility of a telemedical approach in screening retinal diseases.

BACKGROUND: A suitable fundus camera for telemedicine screening can expand the scale of eye care service. The purpose of this study was to compare a handheld nonmydriatic digital fundus camera and a conventional mydriatic fundus camera according to the image quality of their photographs and usability of those photographs to accurately diagnose various retinal diseases. METHODS: A handheld nonmydriatic fundus camera and conventional fundus camera were used to take fundus photographs of outpatients at an ophthalmic clinic before and after pupillary dilation. Image quality and diagnostic agreement of the photos were graded by two masked and experienced retinal specialists. RESULTS: A total of 867 photographs of 393 eyes of 200 patients were collected. Approximately 80% of photos taken under nonmydriasis status using the handheld nonmydriatic fundus camera had good (55.7%) or excellent (22.7%) image quality. The overall agreement of diagnoses between the doctors was more than 90%. When the handheld nonmydriatic fundus camera was used after mydriasis, the proportion of images with good (45%) or excellent (49.7%) quality reached 94.7% and diagnostic agreement was 93.4%. Lens opacity was associated with the quality of images obtained using the handheld camera (p = 0.041), and diagnosis disagreement for handheld camera images was associated with preexisting diabetes diagnosis (p = 0.009). Approximately 40% of patients expressed preference for use of the handheld nonmydriatic camera. CONCLUSION: This study demonstrated the effectiveness of the handheld nonmydriatic fundus camera in clinical practice and its feasibility for telemedicine screening of retinal diseases.

The dynamics of monocytes in the process of collateralization.

Collateralization is an important way for patients with coronary heart disease to supply blood flow to the ischemic area. At present, research on the mechanism of collateral circulation mainly focuses on the inflammatory response. Monocytes are the kernel of inflammatory response during arteriogenesis. Therefore, we reviewed the recent developments in this field in terms of the dynamic changes of monocytes during collateralization. We searched and scanned PubMed for the following terms until November 2018: collateral, collateralization, monocyte, macrophage, and arteriogenesis. Articles were obtained and examined to figure out the dynamics of monocytes in the progress of collateralization. Substantial research shows that recruitment, infiltration, and phenotypic transformation of monocytes can affect function in various ways, respectively. Mechanical or chemical factors that can produce effects on collateral development may be due partly to impact on dynamics of monocytes. Although mechanisms of dynamics of monocytes during arteriogenesis are not elucidated clearly, there is no doubt that deeper exploration of the underlying mechanisms will contribute to pharmaceutical development aiming for promoting collateral development.

Endothelial progenitor cell impairment mediated vasodilation dysfunction via diminishing nitric oxide production in postmenopausal females.

Vascular endothelial dysfunction is the major contributing factor to hypertension. Endothelial progenitor cells (EPCs) are essential for endogenous vascular endothelial renovation. The activity and number of circulating EPCs are preserved in prehypertensive premenopausal females according to our previous research. However, the changes of EPCs in prehypertensive postmenopausal females are poorly understood, and the mechanisms responsible for the loss of the gender protection advantage of cardiovascular disease remain unexplored. In order to determine the effects of EPCs in prehypertensive postmenopausal females, the number and activity of circulating EPCs were tested in the present study. Next, the function of EPCs secreting nitric oxide (NO), vascular endothelial growth factor (VEGF) and granulocyte­macrophage colony­stimulating factor (GM­CSF), as well as their concentration in the plasma, were measured. The association between flow­mediated dilation (FMD) and EPC secretion was also assessed. Attenuation of proliferation and migration of EPCs was observed in prehypertensive patients in comparison with normotensive subjects. In addition, a reduced NO production secreted by EPCs was detected in prehypertensive patients as compared with that in normotensive patients. There was no significant difference in EPC function between postmenopausal females and age­matched males. Finally, the association between FMD and NO production was validated. Collectively, these data indicated that impaired EPCs mediated vasodilation dysfunction via decreasing NO production. Therefore, EPC function enhancement and NO level augmentation are emerging as novel therapeutic strategies for prehypertension therapy.