Consequences Of Endothelial Dysfunction Research Articles

Porphyromonas gingivalis OMVs promoting endothelial dysfunction via the STING pathway in periodontitis.

This study aimed to assess the effects of Porphyromonas gingivalis outer membrane vesicles (Pg-OMVs) in chronic periodontitis and explore the underlying mechanism involved. In vitro, Pg-OMVs were incubated with Ea.hy926 (vessel endothelial cells, ECs) to evaluate their effects on endothelial functions and to investigate the underlying mechanism. The effects of endothelial dysfunction on MG63 osteoblast-like cells were verified using an indirect co-culture method. For invivo studies, micro-CT was conducted to identify alveolar bone mass. Immunofluorescence staining was conducted to confirm the levels of stimulator of interferon genes (STING) in the blood vessel and the number of Runx2+ cells around the alveolar bone. Pg-OMVs were endocytosed by ECs, leading to endothelial dysfunction. The cGAS-STING-TBK1 pathway was activated in ECs, which subsequently inhibited MG63 migration and early osteogenesis differentiation. Invivo, Pg-OMVs promoted alveolar bone resorption, increased STING levels in the blood vessel, and decreased Runx2+ cells around the alveolar bone. Pg-OMVs caused endothelial dysfunction and activated the cGAS-STING-TBK1 signal cascade in ECs, thereby impairing ECs-mediated osteogenesis. Furthermore, Pg-OMVs aggregated alveolar bone loss and altered the blood vessel-mediated osteogenesis with elevated STING.

Study on Red Cell Indices in Chronic Liver Disease in Tertiary Level Hospital

Background: Chronic liver disease (CLD) in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis. Liver diseases are frequently associated with hematological abnormalities. Bleeding and defective blood coagulation contributes to the anemia in CLD patients. Other mechanisms of anemia include aplastic anemia secondary to previous hepatitis, or side effects of treatment of hepatitis with chemotherapeutic agent. Other different factors, such as malabsorption, malnutrition or direct toxic effect also contribute to hematological abnormalities. The examination of complete blood count is common, economically cheap and readily available laboratory procedure. Red cell indices are valuable in the evaluation of morphologic characteristic of anaemias or hematological abnormalities in CLD patients. Objectives: To assess the red cell indices in chronic liver disease patients. Materials & method: This descriptive type of cross-sectional study was conducted in Department of Medicine, Dhaka Medical College Hospital, Dhaka, among 75 cases of Chronic liver disease patients. Samples were selected by purposive sampling technique. Detail demographic data were collected from the patients and recorded in structured case report form. Clinical examination and relevant investigation were done meticulously. Data was processed and analysed with the help of computer program SPSS and Microsoft excel. Quantitative data expressed as mean and standard deviation and qualitative data as frequency and percentage. Results was presented by tabulation and graphical presentation in the form of tables, pie chart, graphs, bar diagrams, histogram & charts etc. Result: Maximum number of patients, 37(49.3%) were between 31-40 years of age with mean age of the patient was 37.58 ± 8.23 years. Out of 75 cases 58(77.0%) patients were male and 17(23.0%) were female. Male-female ratio was 3.34:1. Majority of patients belonged to Child Pugh score B. Prevalence of anaemia was 54(72%) in CLD patients. Microcytic anaemia was predominant and Normocytic anaemia was second most common. Hb concentration & MCV decreases with the severity of Child Pugh score. Abnormalities of red cell indices were positively associated with severity of CLD. Conclusion: Present study concluded that chronic liver diseases are associated with hematological abnormalities. Patients with severe hepatocellular disease develop defects of blood coagulation as a consequence of endothelial dysfunction, thrombocytopenia, deficiencies of coagulation factors and various associated disorders. In overall patients, Child Pugh class C cases had significant low hemoglobin in comparison to rest of group. Assessing the severity and type of anaemia by red cell indices is a useful tool for proper treatment, prognosis in patients of CLD for reducing the mortality and morbidity. J MEDICINE 2024; 25: 41-45

Association of cognitive impairment and arterial hypertension

Impaired cognitive function (CF) is a common manifestation of brain damage as a target organ of arterial hypertension (AH). The presence of hypertension in middle age increases the risk of developing cognitive impairment (CI) and dementia in old age. At the same time, changes in certain indicators characteristic of AH may serve as predictors of CI and dementia in the future. The review presents data on the effects of endothelial dysfunction and increased arterial stiffness on CF. The small number of papers on the effects of hypertension in middle-aged people on the development of CI emphasizes the importance of investigating this topic, as the incidence of CI in young and middle-aged people has increased in recent years.

Association between cardio-ankle vascular index and markers of thrombosis in hospitalized patients COVID-19

To evaluate the relationship between the cardio-ankle vascular index (CAVI) and the marker of procoagulant state - D-dimer in hospitalized patients with coronavirus disease 2019 (COVID-19). This cross-sectional study involved adult patients admitted to the University hospital with clinically diagnosed or laboratory-confirmed COVID-19. We compared groups of patients with normal and elevated CAVI. Univariate and multivariate logistic regression analyses were performed to assess the association between risk factors and elevated D-dimer levels; odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated to determine the strength of association. A p<0.05 was considered statistically significant. The study included 152 patients [64 (42.1%) men and 88 (57.9%) women], mean age 59.10±12.74 years. 45 (29.6%) had elevated CAVI. Patients with elevated CAVI were older, had more comorbid diseases, a higher Charlson comorbidity index and D-dimer levels. Age, the comorbidity index, and CAVI above 9.5 were associated with elevated D-dimer levels in patients with COVID-19. In a multivariate logistic regression, CAVI above 9.5 was an independent predictor of increased D-dimer in patients with COVID-19 (OR 2.513, 95% CI 1.050-6.012; p=0.038). In this study, for the first time, the association between a vascular stiffness marker, elevated CAVI, and increased D-dimer levels in COVID-19 patients was shown. This relationship may be a consequence of endothelial dysfunction and can be used as an additional marker of coagulopathy developing as part of COVID-19.

C-natriuretic peptide – as an indicator of persistent increase in blood pressure in men with hypertension

Annotation. According to multiple studies hypertension (AH) is a multifactorial disease. It is recognized that one of the key mechanisms of persistent increase in blood pressure (BP) is the imbalance between vasoconstriction and vasodilation and endothelial dysfunction (ED) is one of the leading links in the pathogenesis of AH. The consequence of ED is a persistent vasoconstrictor reaction which results in myocardial remodeling in the form of left ventricular hypertrophy (LVH) and the subsequent development of congestive heart failure (CHF). One of the most important representatives of the group of vasoconstrictor peptides is endothelin-1 (ET-1). It has been previously shown that the polymorphism of the gene encoding it (Lys198Asn) is associated with fluctuations in ET-1 plasma concentration. In this regard, the corresponding changes in plasma levels of one of the most powerful vasodilators – C-natriuretic peptide (CNP) – remain poorly understood. CNP is a direct antagonist of ET-1 which increases in the blood in AH and can be used as a screening method to identify patients with high BP. The aim of the study – improving the detection of men with AH who has persistent long-term elevations in BP by using the plasma level of CNP and taking into account the carrier of polymorphic variants of the ET-1 gene. The study involved 191 men aged 40-60 years: 79 men were from control group, 62 patients with AH and LVH and 50 patients with AH complicated by CHF II-III classes for NYHA. Enzyme-linked immunosorbent assay was used to determine the plasma concentration of CNP. Genotyping of the ET-1 gene was performed using the polymerase chain reaction. Mathematical processing was performed on a personal computer using the standard statistical package STATISTICA 6.0. It is established that plasma CNP levels in men with AH and LVH (5.21±0.11) pmol/ml and in patients with AH and CHF (5.22±0.13) pmol/ml are significantly higher than in control patients (2.35±0.06) pmol/ml (p&lt;0.0001) however did not differ in patients with AH from different groups. The obtained results allowed to calculate the limit level of CNP which is ≥3.37 pmol/ml and can be used for screening detection of males with persistently elevated BP in the survey of large populations. It was found that in patients with AH as in the control group the Lys/Lys genotype and the Lys allele of the ET-1 gene predominate. There was no significant difference in the frequency of ET-1 gene between groups (p&gt;0.05). It should be noted that in patients with AH carrying all polymorphic variants of the ET-1 gene the level of CNP in blood was also significantly higher than in the control group, however in carriers of the Asn allele plasma level of CNP is higher than in individuals with the Lys/Lys genotype in all study groups. So it was investigated that the average plasma concentration of CNP in patients with AH is higher than in the control group which made it possible to establish a limit level of peptide for screening of individuals with persistent long-term elevation of BP. In men of the control group and in patients with AH the carrier of the Asn allele of the ET-1 gene is associated with a higher level of CNP but in all study groups the Lys/Lys genotype and the Lys allele of the ET-1 gene were dominant.

Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

Pulmonary hypertension (PH) is likely to complicate chronic obstructive pulmonary disease (COPD) in a large proportion of patients, especially those with severe disease. Majority of patients have a mild to moderate elevation in the pulmonary artery pressure that usually does not require specific treatment. A small subset of patients, however, develops severe PH that is "out-of-proportion" to the severity of COPD. Generally considered a consequence of chronic hypoxaemia, endothelial dysfunction has now been recognised to play an important role in the pathogenesis of PH in COPD. Pulmonary vessels remodelling characterised by intimal enlargement with proliferating smooth muscle cells, medial hypertrophy, arteriolar muscularisation and endothelial cell proliferation, especially affecting the small arterioles and arteries, leads to permanent changes in the vascular structure and function. Clinical recognition of PH is difficult. Echocardiography is used for screening while right heart catheterisation is the gold standard for diagnosis. In patients who have a moderate degree of chronic hypoxaemia, long term oxygen therapy is indicated and is the only therapeutic measure so far known to retard the progress of PH. Newer therapies targeting the specific abnormalities of vasoconstrictor-vasodilator balance, arising as a consequence of endothelial dysfunction, are under investigation and may offer a management option especially in severe PH associated with COPD.

Emerging role of long non-coding RNAs in endothelial dysfunction and their molecular mechanisms.

Long non-coding RNAs (lncRNAs) are the novel class of transcripts involved in transcriptional, post-transcriptional, translational, and post-translational regulation of physiology and the pathology of diseases. Studies have evidenced that the impairment of endothelium is a critical event in the pathogenesis of atherosclerosis and its complications. Endothelial dysfunction is characterized by an imbalance in vasodilation and vasoconstriction, oxidative stress, proinflammatory factors, and nitric oxide bioavailability. Disruption of the endothelial barrier permeability, the first step in developing atherosclerotic lesions is a consequence of endothelial dysfunction. Though several factors interfere with the normal functioning of the endothelium, intrinsic epigenetic mechanisms governing endothelial function are regulated by lncRNAs and perturbations contribute to the pathogenesis of the disease. This review comprehensively addresses the biogenesis of lncRNA and molecular mechanisms underlying and regulation in endothelial function. An insight correlating lncRNAs and endothelial dysfunction-associated diseases can positively impact the development of novel biomarkers and therapeutic targets in endothelial dysfunction-associated diseases and treatment strategies.

Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in Shb-Deficient Endothelial Cells Increases Tumor Lung Metastasis.

Metastasis reflects both the inherent properties of tumor cells and the response of the stroma to the presence of the tumor. Vascular barrier properties, either due to endothelial cell (EC) or pericyte function, play an important role in metastasis in addition to the contribution of the immune system. The Shb gene encodes the Src homology-2 domain protein B that operates downstream of tyrosine kinases in both vascular and immune cells. We have investigated E0771.lmb breast carcinoma metastasis in mice with conditional deletion of the Shb gene using the Cdh5-CreERt2 transgene, resulting in inactivation of the Shb-gene in EC and some hematopoietic cell populations. Lung metastasis from orthotopic tumors, tumor vascular and immune cell characteristics, and immune cell gene expression profiles were determined. We found no increase in vascular leakage that could explain the observed increase in metastasis upon the loss of Shb expression. Instead, Shb deficiency in EC promoted the recruitment of monocytic/macrophagic myeloid-derived suppressor cells (mMDSC), an immune cell type that confers a suppressive immune response, thus enhancing lung metastasis. An MDSC-promoting cytokine/chemokine profile was simultaneously observed in tumors grown in mice with EC-specific Shb deficiency, providing an explanation for the expanded mMDSC population. The results demonstrate an intricate interplay between tumor EC and immune cells that pivots between pro-tumoral and anti-tumoral properties, depending on relevant genetic and/or environmental factors operating in the microenvironment.

Features of autophagy in the cytoplasm of endotheliocytes of blood capillaries in severe burn septicotoxemia

Burn injury and its consequences are an important medical and social problem, given the high mortality and disability rates. The leading cause of death in patients with extensive and deep burns is burn septicotoxemia.Material and methods. The material was the heart muscle of the anterior, posterior and lateral walls of the left ventricle of those who died from burn disease during septicotoxemia. The control group included cases of male mortality as a result of “acute coronary death”. The study of the ultrastructure of endotheliocytes of blood capillaries of the myocardium has been carried out.Results and discussion. Ultrastructural analysis of endotheliocytes of blood capillaries of the myocardium showed that in burn septicotoxemia, intracellular degradation processes are observed in the form of swelling of the cytoplasm and organelles, a decrease in the concentration of vesicular structures, as well as activation of autophagy due to the appearance of autophagosomes and autolysosomes in the cytoplasm. Activation of autophagy should be considered as a naturally developing compensatory reaction aimed at preserving the cellular pool of endotheliocytes of the blood capillaries of the myocardium in response to the alterative effect caused by burn septicotoxemia.Conclusion. The obtained data can serve as a justification for the manifestation of left ventricular contractile insufficiency, which is a consequence of endothelial dysfunction and microcirculatory disorders in the myocardium in burn septicotoxemia.

Diabetes mellitus, platelet function and acetylsalicylic acid

Diabetes mellitus is an independent risk factor for cardiovascular disease (CVD). Accelerated development of atherosclerosis in patients with diabetes is a consequence of endothelial dysfunction, low-grade inflammation, oxidative stress, dyslipidemia, and platelet dysfunction. The results of studies have shown that among diabetic patients there is a high percentage of no effect when using both acetylsalicylic acid (ASA) and clopidogrel. It is necessary to distinguish between patients with a weak response and people with no effect— resistant to aspirin. The frequency of the so-called aspirin resistance, according to modern research, is different and depends on the methods used to study platelet function. In diabetic patients, it ranges from 5 to 45% when taking ASA and from 4 to 30% when taking clopidogrel. Recent studies show an even higher proportion of such individuals among people with diabetes. The appropriateness of lifelong ASA for secondary prevention in people diagnosed with CVD is indisputable (level of evidence A). At the same time, approaches to primary prevention vary in different countries. It is emphasized that the primary prevention with ASA in modern conditions maintains a favorable balance of benefits/risks. The new guidelines state that the calculated 10-year risk of cardiovascular events should not be considered when deciding whether to prescribe ASA to patients without CVD. Instead, all risk factors present in each patient should be considered, including burdensome family history, inability to achieve lipid and glycemic levels, and coronary calcification. The conclusion that ASA has evidence-based efficacy in secondary prophylaxis in patients with CVD has been confirmed. Regarding the primary prevention of cardiovascular events, including healthy individuals, the appropriateness, duration of administration, and choice of ASA should be determined taking into account the 10-year development of serious events, the presence of comorbidities, and the risk of bleeding.

Патофизиологические аспекты формирования «порочного круга» при повреждении клеток печени и развитии цирроза

This review highlights fundamental knowledge about the processes within a damaged liver cell, mechanisms of fi bro- and angiogenesis, as well as hypoxia and hypoxemia. Th e causes and consequences of endothelial dysfunction, the role of cytokines in vascular remodeling and the formation of hemodynamic disorders are described. Th ese changes lead to disorder of local and systemic hemodynamics in case of liver cirrhosis. Such complications as: hepatopulmonary syndrome and portopulmonary hypertension are also described.

The Contribution of Endothelial Dysfunction in Systemic Injury Subsequent to SARS-Cov-2 Infection.

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is associated, alongside with lung infection and respiratory disease, to cardiovascular dysfunction that occurs at any stage of the disease. This includes ischemic heart disease, arrhythmias, and cardiomyopathies. The common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events is represented by coagulation abnormalities and disruption of factors released by endothelial cells, which contribute in maintaining the blood vessels into an anti-thrombotic state. Thus, early alteration of the functionality of endothelial cells, which may be found soon after SARS-CoV-2 infection, seems to represent the major target of a SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to a detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with the ACE2 receptor located in the endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function, which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels. This highlights systemic hypoxia and further aggravates the vicious circle that compromises the development of the disease, leading to irreversible tissue damage and death of people with SARS CoV-2 infection. The review aims to assess some recent advances to define the crucial role of endothelial dysfunction in the pathogenesis of vascular complications accompanying SARS-CoV-2 infection. In particular, the molecular mechanisms associated with the interaction of SARS CoV-2 with the ACE2 receptor located on the endothelial cells are highlighted to support its role in compromising endothelial cell functionality. Finally, the consequences of endothelial dysfunction in enhancing pro-inflammatory and pro-thrombotic effects of SARS-CoV-2 infection are assessed in order to identify early therapeutic interventions able to reduce the impact of the disease in high-risk patients.

Organizational reserves saving the population's health from diseases of the circulatory system

Modern approaches to public health protection in the world are increasingly focused on health conservation, which involves focusing health care efforts on prevention. Timely identification of patients with arterial hypertension (AH) and provision of effective medical care is the main organizational reserve for preventing health losses. Based on the concept of "cardiovascular continuum", analysis of literature sources and the study itself, organizational measures have been developed to preserve health and prevent health losses and reduce mortality from diseases of the circulatory system. From the perspective of the concept of "cardiovascular continuum", the causes of death from BSC are two parallel interrelated processes: arterial hypertension and atherosclerosis, which are the consequences of endothelial dysfunction. Analysis of literature sources and survey results 123 of experts and healthcare professionals in a number of subjects of the Russian Federation show that adequate and timely medical care to the population at BSK, and a reduction in population systolic blood pressure and the reduction of lepidopteron low-density (LDL) are organizational reserves predotvratit loss health and reduce mortality from CVD. We have developed a set of measures to reduce mortality from circulatory diseases in accordance with the concept of the "cardiovascular continuum" include the following: increase population coverage with BSK medical assistance; medical surveillance and treatment of patients with prehypertension; decreased population levels of cholesterol in arterial hypertension (AH); carrying out of thrombolytic therapy; medical emergency cardiovascular conditions in accordance with the concept of "Golden hour"; improving the provision of medicines to the population, increasing the provision of cardiologists to the population. The implementation of a set of measures in the pilot rural district allowed reducing the total mortality of the population for the year of analysis by 12%.

MiR-181a/b-5p regulates human umbilical vein endothelial cell angiogenesis by targeting PDGFRA.

Type 2 diabetes mellitus (T2DM) is a growing burden in low-and middle-income countries. Changing lifestyles and lack of physical activity are some of the reasons contributing to this epidemic increase. Co-morbidities associated with T2DM are largely due to the complications which arise as a consequence of endothelial dysfunction. Platelet derived growth factor-alpha (PDGFRA) is a protein responsible for cell proliferation, angiogenesis, migration and invasion. Increased levels of PDGFRA have been reported in T2DM. This study assessed the epigenetic regulation of PDGFRA through microRNAs (miR-181a/b-5p).Using a bioinformatics-based approach, we assessed the binding of miR-181a/b-5p to PDGFRA. Experimentally, this binding was confirmed using a dual luciferase reporter assay. Further, we overexpressed miR-181a/b-5p in Human umbilical vein endothelial cells (HUVECs) and the influence of over-expression on cell proliferation, migration and angiogenesis was assessed using in-vitro approaches. The influence of miR-181a/b-5p over expression on cellular apoptosis was ascertained using a TUNEL assay with concomitant changes being observed in the levels of Bcl-2 and cleaved Caspase-3.In HUVECs, PDGFRA is a direct target for miR-181a/b-5p. Over expression of miR-181a/b-5p decreased cellular proliferation, migration, invasion, and tube formation-a surrogate marker for angiogenesis. miR-181a/b-5p may be used as a therapeutic intervention to restrict uncontrolled levels of PDGFRA and thereby rescue the phenotypes of increased cell proliferation, migration, invasion and tube formation. miR-181a/b negatively regulates PDGFRA levels. Significance of the study: T2DM and its associated complications emerge from endothelial dysfunction. The associated phenotypes are regulated by a number of proteins, one such member being, PDGFRA. PDGFRA is in turn regulated by miR-181a/b-5p. Complementation with miR-181a/b-5p resulted in reversion of phenotypes. Thus, miR-181a/b-5p-mediated suppression of PDGFRA may be used as a therapeutic intervention in the management of type 2 diabetes.

Effects of Hypobaric Hypoxia on Endothelial Function and Adiponectin Levels in Airforce Aviators.

Background: Hypobaric hypoxia (HH) increases the risk of high altitude-related illnesses (HARI). The pathophysiological mechanism(s) involved are still partially unknown. Altered vascular reactivity as consequence of endothelial dysfunction during HH might play a role in this phenomenon. Adiponectin exerts protective effect on cardiovascular system since it modulates NO release, antagonizing endothelial dysfunction. Aims of this study, performed in a selected population of airforce aviators, were (1) to investigate whether exposure to acute HH might be associated with endothelial dysfunction and (2) to evaluate whether adiponectin might be involved in modulating this phenomenon. Methods: Twenty aviators were exposed to acute HH in a hypobaric chamber by simulating altitude of 8000 and then 6000 m for 2 hours. Vascular reactivity was evaluated by the EndoPAT test immediately before and after the HH; salivary and blood adiponectin levels were measured. Results: EndoPAT performed immediately after HH divided pilots in two groups: 12 pilots with preserved vascular reactivity and 8 pilots with reduction of vascular reactivity, indicating that HH exposure might cause endothelial dysfunction. Salivary and blood adiponectin levels increased post-HH in a time-dependent manner in all aviators, but the significant increase was observed only in those with preserved vascular reactivity suggesting that HH stimulated release of adiponectin that, in turn, by exerting a protective effect, might reduce endothelial dysfunction. Conclusions: Acute HH may cause endothelial dysfunction due, at least in part, to reduced release of adiponectin. This phenomenon might be involved in pathophysiology of HARI.

Deciphering Endothelial Dysfunction in the HIV-Infected Population.

Cardiovascular disease (CVD), as a possible consequence of endothelial dysfunction, is prevalent among HIV-infected patients despite successful administration of antiretroviral drugs. This warrants the routine clinical assessment of endothelial function in HIV-positive patients to circumvent potential CVD events. Several different non-invasive strategies have been employed to assess endothelial function in clinical research studies yielding inconsistencies among these reports. This review summarises the different techniques used for assessing endothelial function, with a focus on proposed blood-based biomarkers, such as endothelial leukocyte adhesion molecule-1 (E-selectin), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWF), TNF-α, interleukin 6 (IL6) and soluble thrombomodulin (sTM). The identification of suitable blood-based biomarkers, especially those that can be measured using a point-of-care device, would be more applicable in under-resourced countries where the prevalence of HIV is high.

Microvascular endothelial dysfunction in rheumatoid arthritis.

The systemic autoimmune disease rheumatoid arthritis (RA) is characterized by increased cardiovascular mortality and morbidity and is an independent cardiovascular risk factor. Cardiovascular diseases (CVDs) result from accelerated atherogenesis, which is a consequence of endothelial dysfunction in the early stages of the disease. Endothelial dysfunction is a functional and reversible alteration of endothelial cells and leads to a shift in the properties of the endothelium towards reduced vasodilation, a pro-inflammatory state, and proliferative and prothrombotic properties. In RA, endothelial dysfunction can occur in the large vessels (such as the conduit arteries) and in the small vessels of the microvasculature, which supply oxygen and nutrients to the tissue and control inflammation, repair and fluid exchange with the surrounding tissues. Growing evidence suggests that microvascular endothelial dysfunction contributes to CVD development, as it precedes and predicts the development of conduit artery atherosclerosis and associated risk factors. As such, numerous studies have investigated microvascular endothelial dysfunction in RA, including its link with disease activity, disease duration and inflammation, the effect of treatments on endothelial function, and possible circulating biomarkers of microvascular endothelial dysfunction. Such findings could have important implications in the cardiovascular risk management of patients with RA.

Eicosapentaenoic acid ethyl ester improves endothelial dysfunction in type 2 diabetic mice

BackgroundEicosapentaenoic acid (EPA) is thought to have many beneficial effects, such as anti-atherosclerogenic and anti-inflammatory properties. However, few studies have reported its effects of endothelial dysfunction in diabetes and its direct effects on the aorta. Here, we investigated the effects of EPA treatment on impaired endothelium-dependent relaxation of the aorta in KKAy mice, a model of type 2 diabetes.MethodsMale KKAy mice were fed a high-fat (HF) diet for 8 weeks to induce diabetes, after which they were divided into two groups. One group was fed a HF diet, and the other group was fed a HF diet containing EPA ethyl ester (EPA-E, 10 mg/day) for 4 weeks. Then, the vascular reactivities of prepared aortic rings were measured in an organ bath to determine if EPA-E administration changed vascular function in these diabetic mice. In addition, we examined effect of EPA-E and its metabolites to vascular action using aorta separated from C57BL/6 J mice.ResultsAlthough EPA-E administration did not change the plasma glucose and insulin levels in diabetic mice, total cholesterol levels were significantly decreased. The aorta extracted from EPA-E untreated diabetic mice showed impaired endothelium-dependent relaxation in response to acetylcholine (ACh). However, EPA-E administration improved the relaxation response to ACh to the control levels observed in non-diabetic C57BL/6 J mice. On the other hand, endothelium-independent relaxation in response to sodium nitroprusside did not significantly differ among these three groups. The enhanced contractile response by phenylephrine in diabetic mice was not altered by the administration of EPA-E. In addition, the direct administration of EPA-E metabolites such as EPA, docosahexaenoic acid, and docosapentaenoic acid led to vasodilation in the aortic rings of C57BL/6 J mice.ConclusionThese results showed that chronic EPA-E administration prevented the development of endothelial dysfunction in KKAy mice, partly via the direct action of EPA-E metabolites on the aorta.

Abstract TMP94: Dietary Salt Impairs Cognitive Function Through Suppression of Endothelial Nitric Oxide Synthesis and Hippocampal BDNF Signaling

High sodium diet (HSD) is a risk factor for stroke and dementia independent of hypertension, but it remains unclear if dietary salt impairs cognition. To address this question, we fed HSD (8% NaCl) or normal diet (ND; 0.5% NaCl) to males C57BL/6 mice for 12 weeks (n=10/group) and assessed cognitive function. At a novel object recognition task (non-spatial memory) HSD mice failed to identify a new object from a familiar one (ND: 72.4±2%, HSD: 56.4±2%, p&lt;0.05). At the Barnes maze test, HSD mice took longer to locate the escape hole (ND: 26±5sec, HSD: 64±12sec, p&lt;0.05), suggesting impaired spatial memory. Nesting behavior, akin to activities of daily living in humans, was also impaired (ND: 4.6±0.1, HSD: 4.1±0.1, Deacon scale, p&lt;0.05). Since HSD alters endothelial function (Compr Physiol, 6:215, 2015) and endothelial nitric oxide (NO) plays a role in cognition (J Neurosc, 26:11513, 2006), we assessed NO production in isolated brain microvessels using DAF-FM as a marker. In HSD mice, NO levels were markedly reduced (ND: 0.33±0.04, HSD: 0.19±0.02 RFU/μm2, p&lt;0.05) and the NO increase produced by the endothelium-dependent agonist acetylcholine (ACh) was suppressed (ND, Veh: 0.33±0.04, ACh: 0.54±0.05 RFU, p&lt;0.05; HSD, Veh: 0.19±0.02, ACh: 0.25±0.05 RFU/μm2, p&gt;0.05). Endothelial NO participates in synaptic plasticity by contributing to maintain normal levels of the neurotrophic factor BDNF (Eur J Neurosc, 44:2226, 2016). Hippocampal BDNF levels were reduced in HSD mice (-52±3%, p&lt;0.05). Consistent with attenuated BDNF signaling, we also observed reductions in the phosphorylation of the BDNF receptor TrkB (-31±0.1%), and of related signaling molecules (ERK1/2: -36±1%; CREB: -45±1%; p&lt;0.05). Arc, a protein involved in memory formation and dependent on BDNF, was also reduced (-41±1%; p&lt;0.05). The data suggest that HSD-induced endothelial dysfunction leads to reduced NO, which, in turn, suppresses hippocampal BDNF and attendant signaling pathways, resulting in impaired synaptic plasticity and cognitive deficits. The finding that dietary salt has a profound impact of on cognition highlights the harmful effects of endothelial dysfunction on brain health and supports public health efforts to curb salt intake especially in individuals at high vascular risk.

Reduced proliferation of endothelial colony-forming cells in unprovoked venous thromboembolic disease as a consequence of endothelial dysfunction.

BackgroundVenous thromboembolic disease (VTD) is a public health problem. We recently reported that endothelial colony-forming cells (ECFCs) derived from endothelial cells (EC) (ECFC-ECs) from patients with VTD have a dysfunctional state. For this study, we proposed that a dysfunctional status of these cells generates a reduction of its proliferative ability, which is also associated with senescence and reactive oxygen species (ROS).Methods and resultsHuman mononuclear cells (MNCs) were obtained from peripheral blood from 40 healthy human volunteers (controls) and 50 patients with VTD matched by age (20−50 years) and sex to obtain ECFCs. We assayed their proliferative ability with plasma of patients and controls and supernatants of cultures from ECFC-ECs, senescence-associated β-galactosidase (SA-β-gal), ROS, and expression of ephrin-B2/Eph-B4 receptor. Compared with cells from controls, cells from VTD patients showed an 8-fold increase of ECFCs that emerged 1 week earlier, reduced proliferation at long term (39%) and, in passages 4 and 10, a highly senescent rate (30±1.05% vs. 91.3±15.07%, respectively) with an increase of ROS and impaired expression of ephrin-B2/Eph-4 genes. Proliferation potential of cells from VTD patients was reduced in endothelial medium [1.4±0.22 doubling population (DP)], control plasma (1.18±0.31 DP), or plasma from VTD patients (1.65±0.27 DP).ConclusionsAs compared with controls, ECFC-ECs from individuals with VTD have higher oxidative stress, proliferation stress, cellular senescence, and low proliferative potential. These findings suggest that patients with a history of VTD are ECFC-ECs dysfunctional that could be associated to permanent risk for new thrombotic events.