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The aim of the present study was to clarify the endothelial function biomarkers and carotid “intima media” thickness (IMT) changes in relation to (rs5443) and (rs2070744) genes polymorphism in the essential arterial hypertension (EAH). Methods. One-hundred EAH patients (48 – control) participated in the case-control study. Soluble vascular cell adhesion molecule (sVCAM-1), total NO metabolites (NO +NO ), transcriptional activity of gene, endothelium-dependent flow-mediated dilation of the brachial artery (FMD BA), and carotid IMT were studied. (rs5443) and (rs2070744) genotyping was performed by TaqMan probes (CFX96™Real-Time PCR). Results. The connection of (rs2070744) with decreased total NO metabolites (F=71.11; p<0.001), reduced genes transcription activity (F=8.71; p<0.001) and increased sVCAM-1 (F=6.96; p=0.002), especially in the -allele carriers (particularly in -genotype patients with lower NO – 16.46% and 40.88%; p<0.001), lowered the transcription activity of NOS3 gene – 46.03% 7 times (p<0.001), and become higher sVCAM-1 – 35.48% and 89.48% (p<0.001), respectively. ANOVA did not confirm the association of (rs5443) gene with endothelial function and carotid IMT. Severe EAH was associated with increased carotid IMT – 50.0% (p<0.001) and 57.14% (p=0.007), wider carotid arteries – 17.36% (p=0.012) and 21.79% (p=0.004), and decreased NOS3 genes transcription activity – 34.54% (p=0.003). Atherosclerotic plaques were unilateral – 24.77% (χ =5.35; p=0.021) or bilateral – 27.62% (χ =5.79; p=0.016). IMT---gt---0.9 mm was followed by a higher BP (p<0.001), FMD BA 11.80% decrease with compensatory increase in carotid arteries diameters – 17.38% and 21.99% (p<0.001) and sVCAM-1 by 20.49% (p=0.005). (rs2070744), but not (rs5443), gene associated with the essential arterial hypertension severity relying upon the endothelial function impairment and genes reduced transcription activity.

Background: Sarco/endoplasmic reticulum Ca2+-ATPase2 (SERCA2) is impaired in various organs in animal models of diabetes. The purpose of this study was to test the effects of an allosteric SERCA2 activator (CDN1163) on glucose intolerance, hepatosteatosis, skeletal muscle function, and endothelial dysfunction in diabetic (db/db) mice. Methods: Either CDN1163 or vehicle was injected intraperitoneally into 16-week-old male control and db/db mice for 5 consecutive days. Results: SERCA2 protein expression was decreased in the aorta of db/db mice. In isometric tension measurements of aortic rings from db/db mice treated with CDN1163, acetylcholine (ACh)-induced relaxation was improved. In vivo intraperitoneal administrations of CDN 1163 also increased ACh-induced relaxation. Moreover, CDN1163 significantly decreased blood glucose in db/db mice at 60 and 120 min during a glucose tolerance test; it also decreased serum insulin levels, hepatosteatosis, and oxygen consumption in skeletal muscle during the early period of exercise in db/db mice. Conclusions: CDN1163 directly improved aortic endothelial dysfunction in db/db mice. Moreover, CDN1163 improved hepatosteatosis, skeletal muscle function, and insulin resistance in db/db mice. The activation of SERCA2 might be a strategy for the all the tissue expressed SERCA2a improvement of endothelial dysfunction and the target for the organs related to insulin resistance.

Background: Cortisol levels, oxidative stress, and lower cerebral performance seem to be closely related. This study aimed to evaluate the question of whether exam stress affected oxidative stress and endothelial function parameters in the salivary samples of students. Methods: A total of 114 healthy students were recruited. All students were subjected to a 21-item DASS questionnaire to assess perceived stress. Cortisol levels, biomarkers of oxidative stress, and endothelial function were evaluated at T0, during the semester, and T1, in the morning before the exam, in saliva samples. In vitro, HUVECs were stimulated with cortisol, and oxidative stress and endothelial function parameters were evaluated. Results: At T1, cortisol levels were significantly increased compared with the levels during the semester. Moreover, exam results correlated inversely with the DASS score at T1. In addition, NOX2, H2O2 and endothelin-1 significantly increased, while NO bioavailability decreased. In vitro, HUVECs treatment with human cortisol determined the increase of oxidative stress and the decrease of endothelial function, in association with impaired eNOS phosphorylation. Conclusion: NOX2-mediated oxidative stress is a mechanism that could mediate cortisol-induced transient endothelial dysfunction during academic examination. Therefore, strategies to monitor or modulate oxidative stress could help students to reduce the impact of examination-related stress.

Paroxysmal Permeability Disorders (PPDs) are pathological conditions caused by periodic short lasting increase of endothelial permeability, in the absence of inflammatory, degenerative, ischemic vascular injury. PPDs include primary angioedema, idiopathic systemic capillary leak syndrome and some rare forms of localized retroperitoneal-mediastinal edema. to validate a microfluidic device to study endothelial permeability in flow conditions. we designed a microchannel network (the smallest channel is 30μm square section). Human Umbilical Vein Endothelial Cells (HUVECs) were cultured under constant shear stress in the networks. Endothelial permeability assessment was based on interaction of biotinylated fibronectin used as a matrix for HUVECs and FITC-conjugated avidin. The increase in endothelial permeability was identified as changes in fluorescence intensity detected by confocal fluorescent microscopy. The microchannels were constantly perfused with a steady flow of culture medium, ensuring a physiologically relevant level of shear stress at the wall of ~0.2 Pa. Our preliminary results demonstrated that circulation of culture medium or plasma from healthy volunteers was associated with low fluorescence of fibronectin matrix. When bradykinin diluted in culture medium was perfused, an increase in average fluorescence was detected. Our microvasculature model is suitable to study endothelial functions in physiological flow conditions and in the presence of factors like bradykinin known as mediator of several PPDs. Therefore, it can be a promising tool to better understand the mechanisms underlying disorders of endothelial permeability.

Background Atmospheric particulate matter (PM) has been associated with endothelial dysfunction, an early marker of cardiovascular risk. Our aim was to extend this research to a genetically homogenous, geographically stable rural population using location-specific moving-average air pollution exposure estimates indexed to the date of endothelial function measurement. Methods We measured endothelial function using brachial artery flow-mediated dilation (FMD) in 615 community-dwelling healthy Amish participants. Exposures to PM < 2.5 μm (PM 2.5 ) and PM < 10 μm (PM 10 ) were estimated at participants’ residential addresses using previously developed geographic information system-based spatio-temporal models and normalized. Associations between PM exposures and FMD were evaluated using linear mixed-effects regression models, and polynomial distributed lag (PDL) models followed by Bayesian model averaging (BMA) were used to assess response to delayed effects occurring across multiple months. Results Exposure to PM 10 was consistently inversely associated with FMD, with the strongest (most negative) association for a 12-month moving average (− 0.09; 95% CI: − 0.15, − 0.03). Associations with PM 2.5 were also strongest for a 12-month moving average but were weaker than for PM 10 (− 0.07; 95% CI: − 0.13, − 0.09). Associations of PM 2.5 and PM 10 with FMD were somewhat stronger in men than in women, particularly for PM 10 . Conclusions Using location-specific moving-average air pollution exposure estimates, we have shown that 12-month moving-average estimates of PM 2.5 and PM 10 exposure are associated with impaired endothelial function in a rural population.

N-3 polyunsaturated fatty acids (PUFAs) improve endothelial function. The arachidonic acid-derived metabolites (epoxyeicosatrienoic acids (EETs)) are part of the endothelial hyperpolarization factor and are vasodilators independent of nitric oxide. However, little is known regarding the regulation of EET concentration by docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in blood vessels. Sprague-Dawley rats were fed either a control or fish oil diet for 3 weeks. Compared with the control, the fish oil diet improved acetylcholine-induced vasodilation and reduced the protein expression of soluble epoxide hydrolase (sEH), a key EET metabolic enzyme, in aortic strips. Both DHA and EPA suppressed sEH protein expression in rat aorta endothelial cells (RAECs). Furthermore, the concentration of 4-hydroxy hexenal (4-HHE), a lipid peroxidation product of n-3 PUFAs, increased in n-3 PUFA-treated RAECs. In addition, 4-HHE treatment suppressed sEH expression in RAECs, suggesting that 4-HHE (derived from n-3 PUFAs) is involved in this phenomenon. The suppression of sEH was attenuated by the p38 kinase inhibitor (SB203580) and by treatment with the antioxidant N-acetyl-L-cysteine. In conclusion, sEH expression decreased after n-3 PUFAs treatment, potentially through oxidative stress and p38 kinase. Mild oxidative stress induced by n-3 PUFAs may contribute to their cardio-protective effect.

Objective: Prosthetic valve thrombosis (PVT) is a serious complication among patients with prosthetic heart valves. Thrombolytic therapy (TT) is now widely used as first-line treatment for PVT. Endothelial dysfunction has previously been reported in patients with PVT. The aim of this study was to investigate the changes in endothelial function soon after TT in PVT patients. Methods: The study group included 85 patients with PVT [female: 53 (62.3%); age: 48.7+-13.9 years] who were evaluated prospectively before and shortly after TT. All of the patients were evaluated using transthoracic and transesophageal echocardiography. TT was administered in all cases with a low-dose, ultra-slow infusion regimen. Endothelial function was evaluated using a noninvasive measurement of flow-mediated dilatation (FMD) of the brachial artery during reactive hyperemia. Results: The study population included 38 (44.7%) obstructive and 47 (55.3%) non-obstructive PVT patients. The obstructive PVT patients had lower baseline FMD values than the non-obstructive PVT group (5.31+-0.76% vs. 5.87+-0.84%; p=0.003). TT was successful in 79 patients (92.9%). FMD was significantly increased in the successfully thrombolyzed patients after TT (5.65+-0.86% vs. 7.13+-1.26%; p<0.001). There was no significant difference in the FMD values after TT in patients who were unresponsive to TT (5.07+-0.61% vs. 5.38+-0.95%; p=0.371). There was a significant increase in FMD values after TT in patients with obstructive PVT (5.31+-0.76% vs. 8.22+-1.15%; p<0.001). However, this difference was not statistically significant for patients with non-obstructive PVT (5.87+-0.84% vs. 6.11+-0.95%; p=0.276). Conclusion: This study demonstrated that successful TT may contribute to improvement of impaired endothelial function in patients with obstructive PVT.

Coronary artery stenting following balloon angioplasty represents the gold standard in revascularization of coronary artery stenoses. However, stent deployment as well as percutaneous transluminal coronary angioplasty (PTCA) alone causes severe injury of vascular endothelium. The damaged endothelium is intrinsically repaired by locally derived endothelial cells and by circulating endothelial progenitor cells from the blood, leading to re‐population of the denuded regions within several weeks to months. However, the process of re‐endothelialization is often incomplete or dysfunctional, promoting in‐stent thrombosis and restenosis. The molecular and biomechanical mechanisms that influence the process of re‐endothelialization in stented segments are incompletely understood. Once the endothelium is restored, endothelial function might still be impaired. Several strategies have been followed to improve endothelial function after coronary stenting. In this review, the effects of stenting on coronary endothelium are outlined and current and future strategies to improve endothelial function after stent deployment are discussed.

Cellular senescence and the senescence‐associated secretory phenotype (SASP) contribute to age‐related arterial dysfunction, in part, by promoting oxidative stress and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed the efficacy of fisetin, a natural compound, as a senolytic to reduce vascular cell senescence and SASP factors and improve arterial function in old mice. We found that fisetin decreased cellular senescence in human endothelial cell culture. In old mice, vascular cell senescence and SASP‐related inflammation were lower 1 week after the final dose of oral intermittent (1 week on—2 weeks off—1 weeks on dosing) fisetin supplementation. Old fisetin‐supplemented mice had higher endothelial function. Leveraging old p16‐3MR mice, a transgenic model allowing genetic clearance of p16INK4A‐positive senescent cells, we found that ex vivo removal of senescent cells from arteries isolated from vehicle‐ but not fisetin‐treated mice increased endothelium‐dependent dilation, demonstrating that fisetin improved endothelial function through senolysis. Enhanced endothelial function with fisetin was mediated by increased NO bioavailability and reduced cellular‐ and mitochondrial‐related oxidative stress. Arterial stiffness was lower in fisetin‐treated mice. Ex vivo genetic senolysis in aorta rings from p16‐3MR mice did not further reduce mechanical wall stiffness in fisetin‐treated mice, demonstrating lower arterial stiffness after fisetin was due to senolysis. Lower arterial stiffness with fisetin was accompanied by favorable arterial wall remodeling. The findings from this study identify fisetin as promising therapy for clinical translation to target excess cell senescence to treat age‐related arterial dysfunction. Oral intermittent fisetin supplementation reduces vascular cell senescence to improve vascular endothelial function and reduce aortic stiffness in old mice.

Endothelial dysfunction drives obesity‐related complications. Doppler ultrasound measurement of blood flow during 1‐min passive leg movements (PLM) is a valuable non‐invasive tool for assessing endothelial function and nitric oxide (NO)‐mediated vasodilation. The objectives of this work were t o identify endothelial dysfunction biomarkers in young individuals with obesity (OB) using the PLM test; to evaluate the effects of a rehabilitation programme on these biomarkers; and to explore associations between PLM data, oxidative metabolism and blood biomarkers of microvascular impairment. Fifteen male OB (age 17 ± 4 years; body mass 121.4 ± 24.1 kg; body mass index 39.3 ± 7.5 kg m −2 ) were tested before (PRE) and after (POST) a 3‐week multidisciplinary body mass reduction programme. Fifteen age‐matched normal‐weight males (CTRL) underwent PRE measurements. Participants performed an incremental exercise, a PLM test and underwent blood biomarker analysis. Peak oxygen uptake and ventilatory thresholds (mL kg −1  min −1 ) were ∼40% lower in OB versus CTRL ( P  < 0.001) and improved by ∼8% in OB POST versus PRE ( P  < 0.05). Plasma nitrite concentration was lower in OB (0.18 ± 0.09 µmol L −1 ) versus CTRL (0.51 ± 0.49; P  = 0.02). Baseline blood flow, normalized for appendicular muscle mass, was similar between the two groups, whereas peak blood flow, Δpeak (difference between peak and baseline) and the area under the blood flow versus time curve were significantly lower in OB PRE, with improvements in OB POST. Several blood biomarkers of endothelial barrier function and permeability differed in OB versus CTRL. The blunted PLM‐induced hyperaemic response and lower plasma nitrite levels indicate impaired endothelial function in young individuals with obesity, occurring before the onset of cardiovascular and metabolic complications. What is the central question of this study? Can passive leg movement (PLM)‐induced hyperaemia and related biomarkers detect early endothelial dysfunction in young individuals with obesity, and are these parameters modifiable by a short‐term rehabilitation programme? What is the main finding and its importance? Young males with obesity exhibit impaired PLM‐induced hyperaemia and reduced plasma nitrite levels, indicating early endothelial dysfunction. A 3‐week multidisciplinary intervention partially improved vascular responses and oxidative metabolism. These findings support the use of PLM as a non‐invasive tool for early detection and monitoring of endothelial dysfunction, before cardiovascular or metabolic complications arise.