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Current evidence suggests that regenerative v. degenerative endothelial responses can be integrated in a clinical endothelial phenotype, reflecting the net result between damage from risk factors and endogenous repair capacity. We have previously shown that a cocoa flavanol (CF) intervention can improve endothelial function and increase the regenerative capacity of the endothelium by mobilising circulating angiogenic cells in patients with coronary artery disease (CAD). The aim of the present study was to investigate whether CF can lower the levels of circulating endothelial microparticles (EMP), markers of endothelial integrity, along with improvements in endothelial function. The levels of EMP in the frozen plasma samples of CAD patients were measured along with endothelial function (flow-mediated vasodilation, FMD); n 16, FMD data published previously), and these data were compared with those of young (n 12) and age-matched (n 12) healthy control subjects. The CAD patients exhibited significantly increased levels of EMP along with impaired FMD when compared with the healthy control subjects. The levels of CD144+ and CD31+/41− EMP were inversely correlated with FMD (r − 0·67, P= 0·01 and r − 0·59, P= 0·01, respectively). In these CAD patients, the levels of EMP were measured after they had consumed a drink containing 375 mg of CF (high-CF intervention, HiFI) or 9 mg of CF (macro- and micronutrient-matched low-CF control, LoFl) twice daily over a 30-d period in a randomised, double-blind, cross-over study. After 1 month of HiFI, the levels of CD31+/41− and CD144+ EMP decreased ( − 25 and − 23 %, respectively), but not after LoFl. Our data show that flavanols lower the levels of EMP along with higher endothelial function, lending evidence to the novel concept that flavanols may improve endothelial integrity.

An acute bout of exercise can improve endothelial function and insulin sensitivity when measured on the day following exercise. Our aim was to compare acute high-intensity continuous exercise (HICE) to high-intensity interval exercise (HIIE) on circulating endothelial microparticles (EMPs) and insulin sensitivity in overweight/obese men and women. Inactive males (BMI = 30 ± 3, 25 ± 6 yr, n = 6) and females (BMI = 28 ± 2, 21 ± 3 yr, n = 7) participated in three experimental trials in a randomized counterbalanced crossover design: 1) No exercise control (Control); 2) HICE (20 min cycling @ just above ventilatory threshold); 3) HIIE (10 X 1-min @ ∼ 90% peak aerobic power). Exercise conditions were matched for external work and diet was controlled post-exercise. Fasting blood samples were obtained ∼ 18 hr after each condition. CD62E(+) and CD31(+)/CD42b- EMPs were assessed by flow cytometry and insulin resistance (IR) was estimated by homeostasis model assessment (HOMA-IR). There was a significant sex X exercise interaction for CD62E(+) EMPs, CD31(+)/CD42b- EMPs, and HOMA-IR (all P < 0.05). In males, both HICE and HIIE reduced EMPs compared to Control (P ≤ 0.05). In females, HICE increased CD62E(+) EMPs (P < 0.05 vs. Control) whereas CD31(+)/CD42b- EMPs were unaltered by either exercise type. There was a significant increase in HOMA-IR in males but a decrease in females following HIIE compared to Control (P<0.05). Overweight/obese males and females appear to respond differently to acute bouts of high-intensity exercise. A single session of HICE and HIIE reduced circulating EMPs measured on the morning following exercise in males but in females CD62E(+) EMPs were increased following HICE. Next day HOMA-IR paradoxically increased in males but was reduced in females following HIIE. Future research is needed to investigate mechanisms responsible for potential differential responses between males and females.

Purpose Hypoxia and oxidative stress affect endothelial function. Endothelial microparticles (MP) are established measures of endothelial dysfunction and influence vascular reactivity. To evaluate the effects of hypoxia and antioxidant supplementation on endothelial MP profiles, a double-blind, placebo-controlled trial, during a high altitude expedition was performed. Methods 29 participants were randomly assigned to a treatment group ( n  = 14), receiving vitamin E, C, A, and N -acetylcysteine daily, and a control group ( n  = 15), receiving placebo. Blood samples were obtained at 490 m (baseline), 3530, 4590, and 6210 m. A sensitive tandem mass spectrometry method was used to measure 8-iso-prostaglandin F 2α and hydroxyoctadecadienoic acids as markers of oxidative stress. Assessment of MP profiles including endothelial activation markers (CD62+MP and CD144+MP) and cell apoptosis markers (phosphatidylserine+MP and CD31+MP) was performed using a standardized flow cytometry-based protocol. Results 15 subjects reached all altitudes and were included in the final analysis. Oxidative stress increased significantly at altitude. No statistically significant changes were observed comparing baseline to altitude measurements of phosphatidylserine expressing MP ( p  = 0.1718) and CD31+MP ( p  = 0.1305). Compared to baseline measurements, a significant increase in CD62+MP ( p  = 0.0079) and of CD144+MP was detected ( p  = 0.0315) at high altitudes. No significant difference in any MP level or oxidative stress markers were found between the treatment and the control group. Conclusion Hypobaric hypoxia is associated with increased oxidative stress and induces a significant increase in CD62+ and CD144+MP, whereas phosphatidylserine+MP and CD31+MP remain unchanged. This indicates that endothelial activation rather than an apoptosis is the primary factor of hypoxia induced endothelial dysfunction.

Stent implantation into atherosclerotic coronary vessels impacts on downstream microvascular function and induces the release of particulate debris and soluble substances, which differs qualitatively and quantitatively between native right coronary arteries (RCAs) and saphenous vein grafts on right coronary arteries (SVG-RCAs). We have now quantified the release of microparticles (MPs) during stent implantation into stable atherosclerotic lesions and compared the release between RCAs and SVG-RCAs. In symptomatic, male patients with stable angina and a stenosis in their RCA or SVG-RCA, respectively (n = 14/14), plaque volume and composition were analyzed using intravascular ultrasound before stent implantation. Coronary aspirate was retrieved during stent implantation with a distal occlusion/aspiration device and divided into particulate debris and plasma. Particulate debris was weighed. Platelet-derived MPs (PMPs) were distinguished by flow cytometry as CD41+, endothelium-derived MPs (EMPs) as CD144+, CD62E+ and CD31+/CD41-, leukocyte-derived MPs as CD45+, and erythrocyte-derived MPs as CD235+. In patients with comparable plaque volume and composition in RCAs and SVG-RCAs, intracoronary PMPs and EMPs were increased after stent implantation into their RCAs and SVG-RCAs (CD41+: 2729.6 ± 645.6 vs. 4208.7 ± 679.4 and 2355.9 ± 503.9 vs. 3285.8 ± 733.2 nr/µL; CD144+: 451.5 ± 87.9 vs. 861.7 ± 147.0 and 444.6 ± 74.8 vs. 726.5 ± 136.4 nr/µL; CD62E+: 1404.1 ± 247.7 vs. 1844.3 ± 378.6 and 1084.6 ± 211.0 vs. 1783.8 ± 384.3 nr/µL, P < 0.05), but not different between RCAs and SVG-RCAs. Stenting in stable atherosclerotic lesions is associated with a substantial release not only of PMPs, but also of EMPs in RCAs and SVG-RCAs. Their release does not differ between RCAs and SVG-RCAs. ClinicalTrials.gov NCT01430884.

Numerous studies have shown that non-cell-autonomous regulation of cancer cells is an important aspect of tumorigenesis. Cancer cells need to communicate with stromal cells by humoral factors such as VEGF, FGFs, and Wnt in order to survive. Recently, extracellular vesicles (EVs) have also been shown to be involved in cell-cell communication between cancer cells and the surrounding microenvironment and to be important for the development of cancer. In addition, these EVs contain small noncoding RNAs, including microRNAs (miRNAs), which contribute to the malignancy of cancer cells. Here, we provide an overview of current research on EVs, especially miRNAs in EVs. We also propose strategies to treat cancers by targeting EVs around cancer cells.

Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced cardiovascular risk in type 2 diabetes patients independently of glycemic control. Although angiotensin II (Ang II) and blood-derived microparticles are major mediators of cardiovascular disease, their impact on SGLT1 and 2 expression and function in endothelial cells (ECs) and isolated arteries remains unclear. Methods ECs were isolated from porcine coronary arteries, and arterial segments from rats. The protein expression level was assessed by Western blot analysis and immunofluorescence staining, mRNA levels by RT-PCR, oxidative stress using dihydroethidium, nitric oxide using DAF-FM diacetate, senescence by senescence-associated beta-galactosidase activity, and platelet aggregation by aggregometer. Microparticles were collected from blood of patients with coronary artery disease (CAD-MPs). Results Ang II up-regulated SGLT1 and 2 protein levels in ECs, and caused a sustained extracellular glucose- and Na + -dependent pro-oxidant response that was inhibited by the NADPH oxidase inhibitor VAS-2780, the AT1R antagonist losartan, sotagliflozin (Sota, SGLT1 and SGLT2 inhibitor), and empagliflozin (Empa, SGLT2 inhibitor). Ang II increased senescence-associated beta-galactosidase activity and markers, VCAM-1, MCP-1, tissue factor, ACE, and AT1R, and down-regulated eNOS and NO formation, which were inhibited by Sota and Empa. Increased SGLT1 and SGLT2 protein levels were observed in the rat aortic arch, and Ang II- and eNOS inhibitor-treated thoracic aorta segments, and were associated with enhanced levels of oxidative stress and prevented by VAS-2780, losartan, Sota and Empa. CAD-MPs promoted increased levels of SGLT1, SGLT2 and VCAM-1, and decreased eNOS and NO formation in ECs, which were inhibited by VAS-2780, losartan, Sota and Empa. Conclusions Ang II up-regulates SGLT1 and 2 protein expression in ECs and arterial segments to promote sustained oxidative stress, senescence and dysfunction. Such a sequence contributes to CAD-MPs-induced endothelial dysfunction. Since AT1R/NADPH oxidase/SGLT1 and 2 pathways promote endothelial dysfunction, inhibition of SGLT1 and/or 2 appears as an attractive strategy to enhance the protective endothelial function.

To investigate the impact of obstructive sleep apnea (OSA) on endothelial repair capacity and apoptosis in the absence of potentially confounding factors including obesity. Sixteen patients with a body mass index <30 and newly diagnosed OSA and 16 controls were studied. Circulating levels of endothelial progenitor cells, a marker of endothelial repair capacity, and endothelial microparticles, a marker of endothelial apoptosis, were quantified before and after four-week therapy with continuous positive airway pressure (CPAP). Endothelial cell apoptotic rate was also quantified in freshly harvested venous endothelial cells. Vascular reactivity was measured by flow-mediated dilation. Before treatment, endothelial microparticle levels were greater and endothelial progenitor cell levels were lower in patients with OSA than in controls (P < 0.001 for both). Levels of endothelial microparticles and progenitors cells were inversely related (r = -0.67, P < 0.001). Endothelial progenitor cell levels increased after effective treatment (P = 0.036). In the absence of any co-morbid conditions including obesity, OSA alone impairs endothelial repair capacity and promotes endothelial apoptosis. These early endothelial alterations may underlie accelerated atherosclerosis and increased cardiovascular risk in OSA.

We aimed to study the endothelial dysfunction among children and adolescents with transfusion-dependent β-thalassemia using von Willebrand factor antigen (VWF:Ag) and flow cytometric analysis of circulating CD144+ endothelial microparticles (EMPs) and endothelial progenitor cells (CD34+VEGFR2+) and assess their relation to iron overload, erythropoietin and chelation therapy as well as echocardiographic parameters and carotid intima–media thickness. The VWF:Ag, EMPs, and CD34+VEGFR2+ cells were significantly higher among patients with β-thalassemia than controls (P < .001). The type of chelation and patients’ compliance did not influence the results. No significant correlations were found between the studied vascular markers. Patients with evident heart disease had higher VWF: Ag, EMPs, and CD34+VEGFR2+ cells than those without. Carotid intima–media thickness was increased among patients but not correlated with vascular markers. We suggest that procoagulant EMPs and VWF: Ag are involved in cardiovascular complications in patients with young β-thalassemia. CD34+VEGFR2+ cells were further increased in response to tissue injury contributing to reendothelialization and neovascularization.

The intratumoral microenvironment, or stroma, is of major importance in the pathobiology of pancreatic ductal adenocarcinoma (PDA), and specific conditions in the stroma may promote increased cancer aggressiveness. We hypothesized that this heterogeneous and evolving compartment drastically influences tumor cell abilities, which in turn influences PDA aggressiveness through crosstalk that is mediated by extracellular vesicles (EVs). Here, we have analyzed the PDA proteomic stromal signature and identified a contribution of the annexin A6/LDL receptor-related protein 1/thrombospondin 1 (ANXA6/LRP1/TSP1) complex in tumor cell crosstalk. Formation of the ANXA6/LRP1/TSP1 complex was restricted to cancer-associated fibroblasts (CAFs) and required physiopathologic culture conditions that improved tumor cell survival and migration. Increased PDA aggressiveness was dependent on tumor cell-mediated uptake of CAF-derived ANXA6+ EVs carrying the ANXA6/LRP1/TSP1 complex. Depletion of ANXA6 in CAFs impaired complex formation and subsequently impaired PDA and metastasis occurrence, while injection of CAF-derived ANXA6+ EVs enhanced tumorigenesis. We found that the presence of ANXA6+ EVs in serum was restricted to PDA patients and represents a potential biomarker for PDA grade. These findings suggest that CAF-tumor cell crosstalk supported by ANXA6+ EVs is predictive of PDA aggressiveness, highlighting a therapeutic target and potential biomarker for PDA.

Exosomes and other extracellular microvesicles (ExMVs) have important functions in intercellular communication and regulation. During the course of infection, these vesicles can convey pathogen molecules that serve as antigens or agonists of innate immune receptors to induce host defense and immunity, or that serve as regulators of host defense and mediators of immune evasion. These molecules may include proteins, nucleic acids, lipids, and carbohydrates. Pathogen molecules may be disseminated by incorporation into vesicles that are created and shed by host cells, or they may be incorporated into vesicles shed from microbial cells. Involvement of ExMVs in the induction of immunity and host defense is widespread among many pathogens, whereas their involvement in immune evasion mechanisms is prominent among pathogens that establish chronic infection and is found in some that cause acute infection. Because of their immunogenicity and enrichment of pathogen molecules, exosomes may also have potential in vaccine preparations and as diagnostic markers. Additionally, the ability of exosomes to deliver molecules to recipient cells raises the possibility of their use for drug/therapy delivery. Thus, ExMVs play a major role in the pathogenesis of infection and provide exciting potential for the development of novel diagnostic and therapeutic approaches.