Endothelium-dependent Vasodilation Research Articles

Clinical Effects and Functional State of the Endothelium in Patients with Arterial Hypertension with a Suboptimal Level of K+ in the Dynamics of Treatment with a Potassium-Magnesium Mineral Complex

Today, electrolyte dysbalance plays an important role in the formation and progression of cardiovascular diseases. The risk of development cardiovascular events also depends on potassium and magnesium deficiency. However, the issue of risks and clinical consequences of suboptimal serum potassium remains poorly understood. The objective: to analyze the influence of the mineral complex on the clinical status, serum levels of potassium and magnesium and the functional state of the endothelium, heart rhythm and parameters of the blood lipid spectrum in patients with arterial hypertension (AH) of the 2nd grade. Materials and methods. 60 patients from 43 to 65 years old with grade 2 AH, II stage took part in the study. Patients (36 men and 24 women) were divided into two groups of 30 persons each. Patients of the 1st group received antihypertensive therapy (perindopril 5–10 mg/day or valsartan 80–120 mg/day + hydrochlorothiazide 12.5 mg) and atorvastatin 20 mg/day. Patients of the 2nd group, in addition to the above-mentioned therapy, were prescribed a mineral complex of natural potassium and magnesium, 1 sachet per day for 3 months. Endothelial function was examined for all participants, the peak blood flow index was determined, arterial blood pressure (ABP) and electrocardiogram (ECG) were monitored daily. Results. In patients of the 2nd group, gradual increased levels of K+ and Mg+ in the blood plasma were determined: the median level of K+ increased by 25.9%, and the median Mg+ concentration – by 16.4% (р˂0.01). Endothelium-dependent vasodilatation after three months of potassium-magnesium citrate use became 2.17 times higher than the initial indicator and 1.94 times higher than in the 1st group (p<0.05). In the 2nd group of patients who additionally took the mineral complex, statistically significant positive dynamics of the blood pressure level were found: after 3 months, the median daily systolic blood pressure (SBP) decreased to 133.56 mm Hg. (LQ=131.64; HQ=135.29) (p<0.01). A significant decrease in the medians of both day and night SBP and diastolic blood pressure was also determined (p<0.01). At the same time, compared to the initial values, the number of ectopic arrhythmias decreased: supraventricular extrasystoles – by 47%, single and paired ventricular extrasystoles – by 37.5% and 47.1%, respectively (p<0.01). Positive dynamics of lipid indicators were found in the patients of the 2nd group. Conclusions. Prescribing a mineral complex to patients with AH and a suboptimal level of K+ who receive therapy including a thiazide diuretic has a complex positive effect: it increases the effectiveness of antihypertensive and hypolipidemic therapy, improves the functional state of the endothelium and vasodilatation, reduces the number of heart rhythm disorders and prevents the occurrence of hypokalemia and hypomagnesemia.

Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature

The accumulation of the microtubule-associated tau protein in and around blood vessels contributes to brain microvascular dysfunction through mechanisms that are incompletely understood. Delivery of nutrients to active neurons in the brain relies on capillary calcium (Ca2+) signals to direct blood flow. The initiation and amplification of endothelial cell Ca2+ signals require an intact microtubule cytoskeleton. Since tau accumulation in endothelial cells disrupts native microtubule stability, we reasoned that tau-induced microtubule destabilization would impair endothelial Ca2+ signaling. We tested the hypothesis that tau disrupts the regulation of local cerebral blood flow by reducing endothelial cell Ca2+ signals and endothelial-dependent vasodilation. We used a pathogenic soluble tau peptide (T-peptide) model of tau aggregation and mice with genetically encoded endothelial Ca2+ sensors to measure cerebrovascular endothelial responses to tau exposure. T-peptide significantly attenuated endothelial Ca2+ activity and cortical capillary blood flow in vivo. Further, T-peptide application constricted pressurized cerebral arteries and inhibited endothelium-dependent vasodilation. This study demonstrates that pathogenic tau alters cerebrovascular function through direct attenuation of endothelial Ca2+ signaling and endothelium-dependent vasodilation.

Preoperative endothelial dysfunction for the prediction of acute kidney injury after cardiac surgery using cardiopulmonary bypass: a pilot study based on a second analysis of the MONS study

BackgroundUp to 42% of patients develop acute kidney injury (AKI) after cardiac surgery. The aim of this study was to describe the relationship between preoperative microcirculatory function and postoperative AKI after cardiac surgery using cardiopulmonary bypass (CPB).MethodsThe prospective observational cohort MONS enrolled 60 patients scheduled for valvular (n = 30, 50%) or coronary (n = 30, 50%) surgery using CPB. Preoperative microcirculation was assessed during preoperative consultation from January 2019 to April 2019 at the University Hospital of Angers, France, using endothelium-dependent and endothelium-independent reactivity tests on the forearm (iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP), respectively). Skin blood flow was measured by laser speckle contrast imaging. The primary endpoint was the occurrence of AKI according to the KDIGO classification during the hospital stay.ResultsForty-three (71.7%) patients developed AKI during the in-hospital follow-up, and 15 (25%) were classified as KDIGO stage 1, 20 (33%) KDIGO stage 2, and 8 (13%) KDIGO stage 3. Regarding preoperative microcirculation, a higher peak amplitude of vasodilation in response to iontophoresis of ACh was found in patients with postoperative occurrence of AKI (35 [20–49] vs 23 [9–44] LSPU, p = 0.04). Iontophoresis of SNP was not significantly different according to AKI occurrence (34 [22–49] vs 36 [20–50] LSPU, p = 0.95). In a multivariable model, the preoperative peak amplitude at iontophoresis of ACh was independently associated with postoperative AKI (OR 1.045 [1.001–1.092], p = 0.045).ConclusionsThe preoperative peak amplitude of endothelium-dependent vasodilation is independently associated with the postoperative occurrence of AKI.Trial registrationClinical-Trials.gov, NCT03631797. Registered 15 August 2018, https://clinicaltrials.gov/ct2/show/NCT03631797

Lipid droplets in the endothelium: The missing link between metabolic syndrome and cardiovascular disease?

The physiology of lipid droplets (LDs) has been most extensively characterized in adipocytes, but LDs also accumulate in endothelial cells lining blood vessels in response to changing levels of triglycerides. In recent issues of the JCI, two independent papers highlight a direct role of endothelial LDs in the genesis of hypertension and atherosclerosis in rodent models. Kim et al. demonstrated that accumulation of LDs in the endothelium leads to hypertension, impairs endothelial function, and accelerates atherosclerosis. Boutagy, Gamez-Mendez, et al. knocked out Atgl in the endothelium and confirmed triglyceride accumulation in endothelial cells that was associated with reduced NO synthesis and impaired endothelial-dependent vasodilation. These data suggest that enhancing triglyceride breakdown in the endothelium could provide a treatment target for patients with metabolic syndrome.

Evidence of premature vascular dysfunction in young adults who regularly use e-cigarettes and the impact of usage length

BackgroundElectronic (e-) cigarettes are increasingly popular tobacco products on the US market. Traditional tobacco products are known to cause vascular dysfunction, one of the earliest indicators of cardiovascular disease (CVD) development. However, little is known about the effect of regular e-cigarette use on vascular function. The purpose of this study was to investigate the impact of regular e-cigarette use on vascular function and cardiovascular health in young, healthy adults.MethodsTwenty-one regular users of e-cigarettes (ECU) and twenty-one demographically matched non-users (NU) completed this study. Vascular health was assessed in the cutaneous microcirculation through different reactivity tests to evaluate overall functionality, endothelium-dependent vasodilation (EDD), and endothelium-independent vasodilation (EID). Macrovascular function was assessed using flow-mediated dilation (FMD).ResultsOur results suggest that regular users of e-cigarettes present with premature microvascular impairment when compared to non-users. Specifically, they exhibit lower hyperemic (p = 0.003), thermal (p = 0.010), and EDD (p = 0.004) responses. No differences in EID between the groups were identified. We also identified that individuals who use e-cigarettes for longer than 3 years also present with systemic manifestations, as observed by significantly reduced macrovascular (p = 0.002) and microvascular (p ≤ 0.044) function.ConclusionsOur novel data suggests that young, apparently healthy, regular users of e-cigarettes present with premature vascular dysfunction in the microcirculation when compared to non-users. We have also identified systemic vascular dysfunction affecting both the micro and macrovasculature in those young individuals who used e-cigarettes for longer than 3 years. Taken together, these findings associate regular e-cigarette use with premature vascular dysfunctions and adverse cardiovascular outcomes.

Activation of ATP-sensitive potassium channels prevents doxorubicin-induced mitochondrial dysfunction in the heart and impaired vascular responses in rats

One of the side effects of the anticancer drug doxorubicin is its mitotoxicity. At the same time, a sufficient number of functioning mitochondria is required for normal energy supply to the heart. The system of ATP-sensitive potassium channels (KATP -channels) of cytoplasmic and mitochondrial membranes is considered to be the central metabolic sensor of energy supply, and their opening triggers mechanisms of protection against cell damage and death under the influence of pathological factors. The aim of our study was to investigate the effect of KATP-channel opener flocalin on doxorubicin-induced mitochondrial dysfunction in the heart, impaired vascular contraction-relaxation function, and oxidative stress. Acute cardiotoxicity was modelled by short-term intraperitoneal injection of doxorubicin in a total dose of 15 mg/kg. To prevent damage, animals were administered flocalin at a dose of 2.5 mg/kg for 5 consecutive days. It was found that the rate of formation of superoxide anion (•O2 - ) and hydroxyl radical (•OH) in the heart mitochondria significantly increased after administration of doxorubicin by 10.5 and 3.4 times, respectively, and the level of H2O2 increased by 5.3 times. When rats were administered flocalin against the background of doxorubicin, oxidative stress indicators were significantly reduced, namely, the rate of •O2 - and •ON generation was 4 and 1.6 times lower, respectively, and the H2O2 levels were 4.6 times lower. Under conditions of impaired redox status in the rat heart after doxorubicin administration, mitochondrial permeability transition pore opening was activated: the amplitude of spontaneous swelling doubled, and Ca2+-induced swelling increased 1.5-fold. The use of flocalin reduced the amplitude of mitochondrial swelling in calcium-free medium by 84.6%, and under the conditions of action inducer of mPTP opening calcium, this index was restored to control values. Endothelium-dependent relaxation of aorta preparations of doxorubicin-treated animals to acetylcholine (0.1 μmol/l) was 47% less than in the control group. Contractions of aortic rings in these animals under the influence of norepinephrine (10 μmol/l) were reduced by 59% compared to control rats. When flocalin, a KATP-channel opener, was injected into rats, the contractile responses of isolated rat aortic rings were restored almost to the values of control animals, while the endothelium-dependent vasodilator effects of acetylcholine (0.1 μmol/l) under the influence of flocalin were restored by 69% compared with animals injected with doxorubicin. Thus, the opening of KATP-channels by flocalin prevents doxorubicininduced mitochondrial dysfunction in the heart, reduces oxidative stress and prevents vascular contractionrelaxation disorders.

Adiponectin secretion by perivascular adipose tissue supports impaired vasodilation in a mouse model of accelerated vascular smooth muscle cell and adipose tissue aging

ObjectivePerivascular adipose tissue (PVAT) function during aging has not been investigated in detail so far and its effect on vasodilation remains to be fully elucidated. The aim of this study was to investigate endothelium-dependent vasodilation of thoracic aorta in a mouse model of accelerated, selective vascular smooth muscle and PVAT aging, induced by SM22α-Cre-driven genetic deletion of the endonuclease ERCC1 (SMC-KO mice) versus healthy littermates (LM). We hypothesized that PVAT enhances vasodilation in LM, possibly through adiponectin secretion, which might be compromised in SMC-KO animals. MethodsThoracic aorta was isolated from SMC-KO animals and LM and segments with and without PVAT were mounted in wire myography setups. The endothelium-dependent vasodilation was assessed via acetylcholine dose-response curves and pathway contribution was studied. Moreover, adiponectin secretion was measured after stimulating the aortic segments with PVAT with acetylcholine. ResultsAdiponectin, secreted by PVAT, led to increased NO-contribution to endothelium-dependent vasodilation in healthy LM, although this did not increase maximum relaxation due to loss of EDH. Endothelium-dependent vasodilation was decreased in SMC-KO animals due to reduced NO-contribution and complete EDH loss. Despite strong lipodystrophy the PVAT partially compensated for lost vasodilation in SMC-KO. LM PVAT contained acetylcholinesterase that attenuated acetylcholine responses. This was lost in SMC-KO. ConclusionsPVAT-derived adiponectin is able to partially compensate for age-related decline in NO-mediated vasodilation, even during strong lipodystrophy, in conditions of absence of compensating EDH. In aorta with healthy PVAT acetylcholinesterase modulates vascular tone, but this is lost during aging, further compensating for decreased acetylcholine responsiveness. Thus, preservation of adiponectin levels, through relatively increased production in lipodystrophic PVAT, and reduction of cholinesterase might be regulatory mechanisms of the PVAT to preserve cholinergic vasodilation during aging.

Inhalation of particulate matter containing environmentally persistent free radicals induces endothelial dysfunction mediated via AhR activation at the air-blood interface.

Particulate matter (PM) containing environmentally persistent free radicals (EPFR) is formed by the incomplete combustion of organic wastes, resulting in the chemisorption of pollutants to the surface of PM containing redox-active transition metals. In prior studies in mice, EPFR inhalation impaired endothelium-dependent vasodilation. These findings were associated with aryl hydrocarbon receptor (AhR) activation in the alveolar type-II (AT-II) cells that form the air-blood interface in the lung. We thus hypothesized that AhR activation in AT-II cells promotes the systemic release of mediators that promote endothelium dysfunction peripheral to the lung. To test our hypothesis, we knocked down AhR in AT-II cells of male and female mice and exposed them to 280 µg/m3 EPFR lo (2.7e + 16 radicals/g) or EPFR (5.5e + 17 radicals/g) compared with filtered air for 4 h/day for 1 day or 5 days. AT-II-AhR activation-induced EPFR-mediated endothelial dysfunction, reducing endothelium-dependent vasorelaxation by 59%, and eNOS expression by 50%. It also increased endothelin-1 mRNA levels in the lungs and peptide levels in the plasma in a paracrine fashion, along with soluble vascular cell adhesion molecule-1 and iNOS mRNA expression, possibly via NF-kB activation. Finally, AhR-dependent increases in antioxidant response signaling, coupled to increased levels of 3-nitrotyrosine in the lungs of EPFR-exposed littermate control but not AT-II AhR KO mice suggested that ATII-specific AhR activation promotes oxidative and nitrative stress. Thus, AhR activation at the air-blood interface mediates endothelial dysfunction observed peripheral to the lung, potentially via release of systemic mediators.

Absorbed Bioactive Compounds Replicate Guanxin II-Induced Endothelium-Associated in/ex vivo Vasodilation.

To develop an interference-free and rapid method to elucidate Guanxin II (GX II)'s representative vasodilator absorbed bioactive compounds (ABCs) among enormous phytochemicals. The contents of ferulic acid, tanshinol, and hydroxysafflor yellow A (FTA) in GX II/rat serum after the oral administration of GX II (30 g/kg) were detected using ultra-performance liquid chromatography-mass spectrometry. Totally 18 rats were randomly assigned to the control group (0.9% normal saline), GX II (30 g/kg) and FTA (5, 28 and 77 mg/kg) by random number table method. Diastolic coronary flow velocity-time integral (VTI), i.e., coronary flow or coronary flow-mediated dilation (CFMD), and endothelium-intact vascular tension of isolated aortic rings were measured. After 12 h of exposure to blank medium or 0.5 mmol/L H2O2, endothelial cells (ECs) were treated with post-dose GX II of supernatant from deproteinized serum (PGSDS, 300 µL PGSDS per 1 mL of culture medium) or FTA (237, 1539, and 1510 mg/mL) for 10 min as control, H2O2, PGSDS and FTA groups. Nitric oxide (NO), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), superoxide dismutase (SOD), malondialdehyde (MDA) and phosphorylated phosphoinositide 3 kinase (p-PI3K), phosphorylated protein kinase B (p-AKT), phosphorylated endothelial nitric oxide synthase (p-eNOS) were analyzed. PGSDS was developed as a GX II proxy of ex vivo herbal crude extracts. PGSDS effectively eliminates false responses caused by crude GX II preparations. When doses equaled the contents in GX II/its post-dose serum, FTA accounted for 98.17% of GX II -added CFMD and 92.99% of PGSDS-reduced vascular tension. In ECs, FTA/PGSDS was found to have significant antioxidant (lower MDA and higher SOD, P<0.01) and endothelial function-protective (lower VEGF, ET-1, P<0.01) effects. The increases in aortic relaxation, endothelial NO levels and phosphorylated PI3K/Akt/eNOS protein induced by FTA/PGSDS were markedly abolished by NG-nitro-L-arginine methyl ester (L-NA, eNOS inhibitor) and wortmannin (PI3K/AKT inhibitor), respectively, indicating an endothelium-dependent vasodilation via the PI3K/AKT-eNOS pathway (P<0.01). This study provides a strategy for rapidly and precisely elucidating GX II's representative in/ex vivo cardioprotective absorbed bioactive compounds (ABCs)-FTA, suggesting its potential in advancing precision ethnomedicine.

Testosterone modulates vasodilation in mesenteric arteries of hypertensive rats

AimsTo evaluate the effects of testosterone on endothelium-dependent vasodilation and oxidative stress in mesenteric resistance arteries. Main methodsSpontaneously hypertensive rats (SHR), aged 8 to 10 weeks, were divided into four groups: intact (SHAM), intact treated with testosterone (TTO; 3 mg/kg/day) via subcutaneous route (s.c.), intact treated with testosterone and anastrozole [aromatase enzyme inhibitor (TTO + ANA; 0.1 mg/kg/day, s.c.)] and intact treated with testosterone and finasteride [5 α-reductase enzyme inhibitor (TTO + FIN; 5 mg/kg/day, s.c.)] for four weeks. Concentration-response curves to acetylcholine (ACh, 0.1 nmol/L - 10 μmol/L) were obtained in mesenteric resistance arteries previously contracted with phenylephrine (PE, 3 μmol/L), before and after the use of selective inhibitors. Reactive oxygen species (ROS) levels were assessed in the vessels and the endothelium analyzed by scanning electron microscopy. Key findingsTTO group showed a lower participation of nitric oxide (NO), increased oxidative stress, and participation of prostanoids and endothelium-dependent hyperpolarization (EDH), possibly to maintain the vasodilator response. Lower participation of NO and prostanoids, combined to an increased participation of EDH, were observed in the TTO + ANA group, in addition to higher levels of ROS and altered endothelial morphology. The vasodilation to ACh was impaired in TTO + FIN, along increased participation of NO, reduction of prostanoids, and greater EDH-dependent vasodilation. SignificanceTestosterone contributes to endothelial vasodilation by enhancing EDH through an increased participation of epoxyeicosatrienoic acids. While the decrease in NO appears to involve the participation of dihydrotestosterone, 17 β-estradiol seems to stimulate the action of the NO pathway and prostanoids.

Influence of a Decrease in Blood Viscosity on Arterial Pressure in Normotensive and Spontaneously Hypertensive Rats.

We investigated the effect of a decrease in blood viscosity on the mean BP during isovolumic hemodilution and vasodilating activity of the endothelium in normotensive Wistar rats and spontaneously hypertensive rats (SHR). Blood viscosity was reduced by isovolumic hemodilution (replacement of 10% of circulating blood with an equal volume of plasma). Hemodilution caused the same reduction in blood viscosity by 16% in both groups of rats. In Wistar rats, a decrease in blood viscosity did not significantly change in the mean BP; no significant correlations between blood viscosity and mean BP were observed before and after hemodilution. In SHR, a decrease in blood viscosity led to a significant decrease in the mean BP by 18%. Correlations were found between the mean BP and blood viscosity in SHR before (r=0.63; p=0.028) and after (r=0.71; p=0.009) isovolumic hemodilution. In SHR, a decrease in the index of vasodilating activity of the endothelium due to a decrease in the vasodilatory response to intravenous administration of the endothelium-dependent vasodilator acetylcholine was revealed. In SHR, BP passively follows the change, in this case, the decrease in blood viscosity, which attests to impaired BP regulation in response to changes in shear stress on the vascular endothelium caused by the development of endothelial dysfunction in hypertensive animals.

Modification of Cardiovascular Risk Factors and the Evolution of The Cardiovascular Phenotype of Liver Transplant Recipients in the Long -Term Postoperative Period.

To evaluate the contribution of traditional and additional cardiovascular risk factors (CVRFs) to the development of chronic ischemic heart disease (CIHD) in liver transplant recipients during the long-term postoperative period. A single-center prospective cohort study was conducted. The study included 740 patients with chronic end-stage liver disease (CESLD) and cirrhotic cardiomyopathy (CCMP). During the observation period (5.4±2.29 years), patients were divided into two groups: liver transplant recipients (n=420) and patients with CESLD on the waiting list who did not receive a donor organ (n=320). In patients enrolled to the study upon inclusion in the waiting list, CVRFs, history, clinical and laboratory and instrumental data were studied at all stages of the hepato-cardiac continuum. During the long-term postoperative period, liver transplant recipients belonged to the group of high cardiovascular risk: over a 5-year observation period, 35.7% (n=150) of them developed metabolic syndrome (MS), 9.8% developed verified CIHD associated with MS. The incidence of traditional CVRFs was high (arterial hypertension, 88.6%; obesity, 36.6%; hypercholesterolemia, 77.8%; hypertriglyceridemia, 43.6%; reduced concentration of high-density lipoprotein cholesterol, 35.4%; increased concentrations of low-density lipoprotein cholesterol, 66.8% and very low-density lipoprotein cholesterol, 51.2%; increased atherogenic index, 61.5%). During the long-term postoperative period as compared to the period when patients were on the waiting list, additional CVRFs appeared: increases in body mass index, calcium index, nitric oxide metabolites, endothelin-1, homocysteine, intercellular adhesion molecules VCAM-1 and ICAM-1, and decreases in endothelium-dependent vasodilation and glomerular filtration rate to less than 60 ml/min/1.73 m2. A model for the development of CIHD was created. The model uses a complex of independent risk factors and demonstrates a predictive accuracy of 84.6%. The study results indicate a modification of CVRFs and a dynamic change in the cardiovascular phenotype of liver transplant recipients: progression of CCMP during their stay on the waiting list, regression of CCMP manifestations during the first 12 months after orthotopic liver transplantation, and increases in the total cardiovascular risk and likelihood of CIHD in the long-term postoperative period.

Histamine H2-receptor antagonism improves conduit artery endothelial function and reduces plasma aldosterone level without lowering arterial blood pressure in angiotensin II–hypertensive mice

Aldosterone through the mineralocorticoid receptor MR has detrimental effects on cardiovascular disease. It reduces the bioavailability of nitric oxide and impairs endothelium-dependent vasodilatation. In resistance arteries, aldosterone impairs the sensitivity of vascular smooth muscle cells to nitric oxide by promoting the local secretion of histamine which activates H2 receptors. The present experiments tested in vivo and ex vivo the hypothesis that systemic H2-receptor antagonism reduces arterial blood pressure and improves vasodilatation in angiotensin II–induced chronic hypertension. Hypertension was induced by intravenous infusion of angiotensin II (60 ng kg−1 min−1) in conscious, unrestrained mice infused concomitantly with the H2-receptor antagonist ranitidine (27.8 µg kg−1 min−1) or vehicle for 24 days. Heart rate and arterial blood pressure were recorded by indwelling arterial catheter. Resistance (mesenteric) and conductance (aortae) arteries were harvested for perfusion myography and isometric tension recordings by wire myography, respectively. Plasma was analyzed for aldosterone concentration. ANGII infusion resulted in elevated arterial blood pressure and while in vivo treatment with ranitidine reduced plasma aldosterone concentration, it did not reduce blood pressure. Ranitidine improved ex vivo endothelial function (acetylcholine 10−9 to 10−6 mol L−1) in mesenteric resistance arteries. This was abolished by ex vivo treatment with aldosterone (10−9 mol L−1, 1 h). In aortic segments, in vivo ranitidine treatment impaired relaxation. Activation of histamine H2 receptors promotes aldosterone secretion, does not affect arterial blood pressure, and protects endothelial function in conduit arteries but promotes endothelial dysfunction in resistance arteries during angiotensin II–mediated hypertension. Aldosterone contributes little to angiotensin II–induced hypertension in mice.

Nur77 mitigates endothelial dysfunction through activation of both nitric oxide production and anti-oxidant pathways

BackgroundNur77 belongs to the member of orphan nuclear receptor 4A family that plays critical roles in maintaining vascular homeostasis. This study aims to determine whether Nur77 plays a role in attenuating vascular dysfunction, and if so, to determine the molecular mechanisms involved. MethodsBoth Nur77 knockout (Nur77 KO) and Nur77 endothelial specific transgenic mice (Nur77-Tg) were employed to examine the functional significance of Nur77 in vascular endothelium in vivo. Endothelium-dependent vasodilatation to acetylcholine (Ach) and reactive oxygen species (ROS) production was determined under inflammatory and high glucose conditions. Expression of genes was determined by real-time PCR and western blot analysis. ResultsIn response to tumor necrosis factor alpha (TNF-α) treatment and diabetes, the endothelium-dependent vasodilatation to Ach was significantly impaired in aorta from Nur77 KO as compared with those from the wild-type (WT) mice. Endothelial specific overexpression of Nur77 markedly prevented both TNF-α- and high glucose-induced endothelial dysfunction. Compared with WT mice, after TNF-α and high glucose treatment, ROS production in aorta was significantly increased in Nur77 KO mice, but it was inhibited in Nur77-Tg mice, as determined by dihydroethidium (DHE) staining. Furthermore, we demonstrated that Nur77 overexpression substantially increased the expression of several key enzymes involved in nitric oxide (NO) production and ROS scavenging, including endothelial nitric oxide synthase (eNOS), guanosine triphosphate cyclohydrolase 1 (GCH-1), glutathione peroxidase-1 (GPx-1), and superoxide dismutases (SODs). Mechanistically, we found that Nur77 increased GCH1 mRNA stability by inhibiting the expression of microRNA-133a, while Nur77 upregulated SOD1 expression through directly binding to the human SOD1 promoter in vascular endothelial cells. ConclusionOur results suggest that Nur77 plays an essential role in attenuating endothelial dysfunction through activating NO production and anti-oxidant pathways in vascular endothelium. Targeted activation of Nur77 may provide a novel therapeutic approach for the treatment of cardiovascular diseases associated with endothelial dysfunction.

High dietary salt intake attenuates nitric oxide mediated endothelium-dependent vasodilation and increases oxidative stress in pregnancy.

This study aimed to investigate the impact of dietary salt intake during normal pregnancy on maternal microvascular and macrovascular endothelium-dependent reactivity and oxidative stress level. In this cross-sectional study, based on their 24-h urinary sodium excretion, pregnant women (37-40 weeks of gestation) were divided into three groups: normal salt (<5.75 g/day, N = 12), high salt (5.75-10.25 g/day, N = 36), and very high salt (VHS;>10.25 g/day, N = 17). Forearm skin microvascular reactivity in response to vascular occlusion, local heating (LTH) and iontophoresis of acetylcholine (AChID), as well as brachial artery flow mediated dilation (FMD) were measured. Serum nitric oxide, endocan, 8-iso-prostaglandin F2α (8-iso-PGF2α), thiobarbituric acid reactive substances (TBARS), and ferric-reducing ability of plasma assay were measured as biomarkers of endothelial function/activation and oxidative stress. Brachial artery FMD, microvascular AChID, and LTH were significantly decreased in VHS compared with NS group, while LTH was also decreased in normal salt compared with high salt group. Nitric oxide was significantly decreased in both high salt and VHS groups compared with normal salt. Endocan, 8-iso-PGF2α, and TBARS were significantly increased in VHS compared with the normal salt group. High dietary salt intake is associated with decreased nitric oxide mediated endothelium-dependent vasodilation in peripheral microcirculation and macrocirculation of healthy pregnant women due to increased oxidative stress.

The oxidized phospholipid PGPC impairs endothelial function by promoting endothelial cell ferroptosis via FABP3

Ferroptosis is a novel cell death mechanism that is mediated by iron-dependent lipid peroxidation. It may be involved in atherosclerosis development. Products of phospholipid oxidation play a key role in atherosclerosis. 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) is a phospholipid oxidation product present in atherosclerotic lesions. It remains unclear whether PGPC causes atherosclerosis by inducing endothelial cell ferroptosis. In this study, human umbilical vein endothelial cells (HUVECs) were treated with PGPC. Intracellular levels of ferrous iron, lipid peroxidation, superoxide anions (O2•−), and glutathione were detected, and expression of fatty acid binding protein-3 (FABP3), glutathione peroxidase 4 (GPX4), and CD36 were measured. Additionally, the mitochondrial membrane potential (MMP) was determined. Aortas from C57BL6 mice were isolated for vasodilation testing. Results showed that PGPC increased ferrous iron levels, the production of lipid peroxidation and O2•−, and FABP3 expression. However, PGPC inhibited the expression of GPX4 and glutathione production and destroyed normal MMP. These effects were also blocked by ferrostatin-1, an inhibitor of ferroptosis. FABP3 silencing significantly reversed the effect of PGPC. Furthermore, PGPC stimulated CD36 expression. Conversely, CD36 silencing reversed the effects of PGPC, including PGPC-induced FABP3 expression. Importantly, E06, a direct inhibitor of the oxidized 1-palmitoyl-2-arachidonoyl-phosphatidylcholine IgM natural antibody, inhibited the effects of PGPC. Finally, PGPC impaired endothelium-dependent vasodilation, ferrostatin-1 or FABP3 inhibitors inhibited this impairment. Our data demonstrate that PGPC impairs endothelial function by inducing endothelial cell ferroptosis through the CD36 receptor to increase FABP3 expression. Our findings provide new insights into the mechanisms of atherosclerosis and a therapeutic target for atherosclerosis.

Diagnostic criteria of endothelial dysfunction, subclinical atherosclerosis and their relationship with NOS3 and HIF1A gene polymorphism in military personnel in extreme conditions of the arctic zone

The state of the arterial vascular endothelium against the background of subclinical atherosclerosis and its relationship with gene polymorphism in military personnel serving in the Arctic climatic zone, depending on the duration of service, was evaluated. In total, 251 male servicemen aged 28–40 years were examined. The group of servicemen of the Arctic climate zone included 99 people, who were divided into three groups according to the duration of military service in the Arctic: group 1 included 8 (8%) servicemen with up to 5 years of military service; group 2, 21 (21%) people with 5–10 years; group 3, 70 (71%) servicemen with 10 years. The control group included 152 military personnel aged 28–40 years from the temperate climate zone. All participants underwent a test with reactive hyperemia, elastography, measurement of the thickness of the intima–media complex on the brachial artery, ultrasound examination of the common carotid arteries, photoplethysmography, pulse oximetry, spirometry, anthropometry, biochemical blood analysis, and determination of gene polymorphism using polymerase chain reaction. The results revealed that endothelium-dependent vasodilation rats in groups 2 and 3 were 1. 7 and 2. 7 times less than that in group 1 (p 0. 05). In 11 (16%) military personnel of group 3, thickening of the intima–media complex was found in 50% of the adjacent areas of the common carotid arteries. In groups 2 and 3, the total blood cholesterol level exceeded the value by 10% and 14%, respectively, compared with group 1 (p 0. 05). The artery wall was rigid in carriers of the T/T genotypes of the HIF1A and NOS3 genes and was most elastic in the G/T genotypes of the NOS3 gene and C/C of the HIF1A gene. In general, military personnel serving in the Arctic climatic zone with a service duration of 10 years have endothelial dysfunction and peripheral vascular stiffness with subclinical atherosclerosis phenomena, particularly in military personnel with the T/T genotypes of HIF1A (rs11549465) and NOS3 (rs1799983). We believe that the leading pathogenetic link of endothelial dysfunction of arterial vessels is the resistance of myocytes to the effects of vasodilation factors expressed by the vascular endothelium, particularly nitric oxide. The longer the service experience of military personnel under conditions of polar hypoxia, the higher the probability of developing endothelial dysfunction.

Aging related decreases in NM myosin expression and contractility in a resistance vessel.

Introduction: Vasodilatation in response to NO is a fundamental response of the vasculature, and during aging, the vasculature is characterized by an increase in stiffness and decrease in sensitivity to NO mediated vasodilatation. Vascular tone is regulated by the activation of smooth muscle and nonmuscle (NM) myosin, which are regulated by the activities of myosin light chain kinase (MLCK) and MLC phosphatase. MLC phosphatase is a trimeric enzyme with a catalytic subunit, myosin targeting subunit (MYPT1) and 20kDa subunit of unknown function. Alternative mRNA splicing produces LZ+/LZ- MYPT1 isoforms and the relative expression of LZ+/LZ- MYPT1 determines the sensitivity to NO mediated vasodilatation. This study tested the hypothesis that aging is associated with changes in LZ+ MYPT1 and NM myosin expression, which alter vascular reactivity. Methods: We determined MYPT1 and NM myosin expression, force and the sensitivity of both endothelial dependent and endothelial independent relaxation in tertiary mesenteric arteries of young (6mo) and elderly (24mo) Fischer344 rats. Results: The data demonstrate that aging is associated with a decrease in both the expression of NM myosin and force, but LZ+ MYPT expression and the sensitivity to both endothelial dependent and independent vasodilatation did not change. Further, smooth muscle cell hypertrophy increases the thickness of the medial layer of smooth muscle with aging. Discussion: The reduction of NM myosin may represent an aging associated compensatory mechanism to normalize the stiffness of resistance vessels in response to the increase in media thickness observed during aging.

Effect of cigarette smoking on lipid profile, high sensitivity c-reactive protein, and malondialdehyde

Background: One of the most common reasons for preventable mortality is the smoking habit. Cigarette smoke promotes the process of atherogenesis by producing oxygen-derived free radicals which cause damage to the lipids. Cigarette smoking is associated with impaired endothelium-dependent vasodilatation and cardiovascular disease (CVD). Aims and Objectives: The objectives of the study were the following: (i) to compare the levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very LDL (VLDL) in asymptomatic male smokers and non-smokers of the age group 25–50 years; (ii) to determine and compare the levels of high sensitivity C-reactive protein (hs-CRP) in the above two groups, and (iii) to study and compare the levels of malondialdehyde (MDA) in the above groups. Materials and Methods: The study was conducted on 60 males in which 30 smokers and 30 non-smokers of the age group 25–50 years were incorporated. It was a cross-sectional comparative study, which included the participants who met all the inclusion and exclusion criteria. Before the conduct of the study, informed consent was obtained from all the participants. Moreover, the selection of participants was done in a consecutive manner until the sample size was achieved. TC and TGs were estimated by the enzymatic colorimetric method, HDL cholesterol by the phosphotungstic acid method, and LDL and VLDL by Friedwald’s formula. MDA was determined by spectrophotometry and hs-CRP by the immunoturbidometric method. The data acquired were analyzed by utilizing the Statistical Package for the Social Sciences version 18. Results: Dyslipidemia was seen in smokers as evidenced by significantly elevated levels of TC, TG, LDL, and VLDL; and significantly reduced levels of HDL. The mean values of hs-CRP were significantly elevated in smokers when compared to that of non-smokers. Oxidative stress was increased in subjects who were smokers. The mean values of MDA were significantly elevated in the smokers. Conclusion: The smoking habit is associated with dyslipidemia, oxidative stress, and inflammation which predisposes to the development of endothelial dysfunction and atherosclerosis. The significance of early screening measures to be undertaken in asymptomatic smokers for dyslipidemia, oxidative stress, and hs-CRP is unveiled by the present study. Therefore, early screening can be used to advise smokers to refrain from smoking to avoid complications of CVDs, so that they can upgrade the quality of their life.

Physalis minima leaf extract improves endothelium-dependent vasodilation and decreases blood pressure in ovariectomized rats

This study examined the impact of methanol extract of Physalis minima leaf (MEP) on vascular function and blood pressure in ovariectomized (OVX) rats simulating postmenopausal syndrome. Thirty Wistar rats underwent bilateral ovariectomy. After five weeks, OVX rats were divided into groups, receiving MEP at doses of 500, 1,500, and 2,500 mg/kg BW for four weeks. Two groups served as OVX controls (5-week and 9-week OVX rats). Six sham-operated rats were included as a control. Thoracic aortic rings were isolated for endothelium-dependent vascular relaxation analysis. Endothelial cell count was determined via hematoxylin-eosin staining. Systolic blood pressure (SBP) was measured using a tail-cuff method. Results showed significant (p &lt; 0.01) vascular relaxation decline in 9-week OVX rats. MEP at 1,500 and 2,500 mg/kg BW restored vascular dilation. Endothelial cell number decreased significantly (p &lt; 0.0001) in 5-week and 9-week OVX rats. MEP at 2,500 mg/kg BW raised endothelial cell numbers significantly (p &lt; 0.0001). SBP increased significantly (p &lt; 0.0001) in 9-week OVX rats. MEP at 1,500 mg/kg BW lowered SBP, nearing sham levels, while 2,500 mg/kgBW further reduced SBP significantly (p &lt; 0.0001). Physalis minima extract has the potential to treat postmenopausal vascular issues and hypertension. The strong hypotensive effect at the highest dose emphasizes dosage determination and potential side effects investigation.