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1.
Role of oxylipins generated from dietary PUFAs in the modulation of endothelial cell function.
Du, Y, Taylor, CG, Aukema, HM, Zahradka, P
Prostaglandins, leukotrienes, and essential fatty acids. 2020;:102160
Abstract
Oxylipins, which are circulating bioactive lipids generated from polyunsaturated fatty acids (PUFAs) by cyclooxygenase, lipooxygenase and cytochrome P450 enzymes, have diverse effects on endothelial cells. Although studies of the effects of oxylipins on endothelial cell function are accumulating, a review that provides a comprehensive compilation of current knowledge and recent advances in the context of vascular homeostasis is lacking. This is the first compilation of the various in vitro, ex vivo and in vivo reports to examine the effects and potential mechanisms of action of oxylipins on endothelial cells. The aggregate data indicate docosahexaenoic acid-derived oxylipins consistently show beneficial effects related to key endothelial cell functions, whereas oxylipins derived from other PUFAs exhibit both positive and negative effects. Furthermore, information is lacking for certain oxylipin classes, such as those derived from α-linolenic acid, which suggests additional studies are required to achieve a full understanding of how oxylipins affect endothelial cells.
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2.
Pharmacokinetic Parameters of Watermelon (Rind, Flesh, and Seeds) Bioactive Components in Human Plasma: A Pilot Study to Investigate the Relationship to Endothelial Function.
Fan, J, Park, E, Zhang, L, Edirisinghe, I, Burton-Freeman, B, Sandhu, AK
Journal of agricultural and food chemistry. 2020;(28):7393-7403
Abstract
This study aimed to investigate the metabolic fate of bioactive components in watermelon and explore their effect on endothelial function. Six healthy overweight/obese (BMI: 28.7 ± 1.6 kg/m2) adults received 100 kcal of watermelon flesh (WF), rind (WR), seeds (WS), or control meal. l-Citrulline, arginine, and (poly)phenolic metabolites were characterized in plasma over 24 h using UHPLC-MS. Endothelial function was assessed using a flow mediated dilation (FMD) technique over 7 h. Maximum concentration (Cmax) and area under the curve (AUC0-8h) of l-citrulline were significantly higher after WF- and WR-containing test meals compared to control (p < 0.05). Likewise, several individual phenolic metabolites in plasma had significantly higher Cmax after WR, WF, or WS intake compared to control. FMD responses were not different among test meals. Our results provide insights on circulating metabolites from watermelon flesh, seed, and rind and lay the foundation for future clinical trials on vascular benefits of watermelon.
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3.
Promising Anti-atherosclerotic Effect of Berberine: Evidence from In Vitro, In Vivo, and Clinical Studies.
Fatahian, A, Haftcheshmeh, SM, Azhdari, S, Farshchi, HK, Nikfar, B, Momtazi-Borojeni, AA
Reviews of physiology, biochemistry and pharmacology. 2020;:83-110
Abstract
Elevated levels of plasma cholesterol, impaired vascular wall, and presence of inflammatory macrophages are important atherogenic risk factors contributing to atherosclerotic plaque formation and progression. The interventions modulating these risk factors have been found to protect against atherosclerosis development and to decrease atherosclerosis-related cardiovascular disorders. Nutritional approaches involving supplements followed by improving dietary habits and lifestyle have become growingly attractive and acceptable methods used to control atherosclerosis risk factors, mainly high levels of plasma cholesterol. There are a large number of studies that show berberine, a plant bioactive compound, could ameliorate atherosclerosis-related risk factors. In the present literature review, we put together this studies and provide integrated evidence that exhibits berberine has the potential atheroprotective effect through reducing increased levels of plasma cholesterol, particularly low-density lipoprotein (LDL) cholesterol (LDL-C) via LDL receptor (LDLR)-dependent and LDL receptor-independent mechanisms, inhibiting migration and inflammatory activity of macrophages, improving the functionality of endothelial cells via anti-oxidant activities, and suppressing proliferation of vascular smooth muscle cells. In conclusion, berberine can exert inhibitory effects on the atherosclerotic plaque development mainly through LDL-lowering activity and suppressing atherogenic functions of mentioned cells. As the second achievement of this review, among the signaling pathways through which berberine regulates intracellular processes, AMP-activated protein kinase (AMPK) has a central and critical role, showing that enhancing activity of AMPK pathway can be considered as a promising therapeutic approach for atherosclerosis treatment.
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4.
Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries.
Skofic Maurer, D, Zabini, D, Nagaraj, C, Sharma, N, Lengyel, M, Nagy, BM, Frank, S, Klepetko, W, Gschwandtner, E, Enyedi, P, et al
Cells. 2020;(9)
Abstract
Endothelial dysfunction is one of the hallmarks of different vascular diseases, including pulmonary arterial hypertension (PAH). Ion channelome changes have long been connected to vascular remodeling in PAH, yet only recently has the focus shifted towards Ca2+-activated Cl- channels (CaCC). The most prominent member of the CaCC TMEM16A has been shown to contribute to the pathogenesis of idiopathic PAH (IPAH) in pulmonary arterial smooth muscle cells, however its role in the homeostasis of healthy human pulmonary arterial endothelial cells (PAECs) and in the development of endothelial dysfunction remains underrepresented. Here we report enhanced TMEM16A activity in IPAH PAECs by whole-cell patch-clamp recordings. Using adenoviral-mediated TMEM16A increase in healthy primary human PAECs in vitro and in human pulmonary arteries ex vivo, we demonstrate the functional consequences of the augmented TMEM16A activity: alterations of Ca2+ dynamics and eNOS activity as well as decreased NO production, PAECs proliferation, wound healing, tube formation and acetylcholine-mediated relaxation of human pulmonary arteries. We propose that the ERK1/2 pathway is specifically affected by elevated TMEM16A activity, leading to these pathological changes. With this work we introduce increased TMEM16A activity in the cell membrane of human PAECs for the development of endothelial dysfunction in PAH.
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5.
The effect of vitamin E supplementation on biomarkers of endothelial function and inflammation among hemodialysis patients: A double-blinded randomized clinical trial.
Pirhadi-Tavandashti, N, Imani, H, Ebrahimpour-Koujan, S, Samavat, S, Hakemi, MS
Complementary therapies in medicine. 2020;:102357
Abstract
OBJECTIVES The present study was aimed to investigate the effect of alpha-tocopherol supplementation on biomarkers of endothelial function (Intercellular Adhesion Molecule 1 and Vascular Cell Adhesion Protein 1) and inflammatory markers (Interleukin 6 and high-sensitivity C-reactive protein) among the hemodialysis patients. METHODS To conduct this randomized, double-blinded, and placebo-controlled clinical trial, 49 hemodialysis patients, aged 20-60 years, were recruited and randomly divided into the intervention and control groups. The intervention group (n = 25) received 600 IU alpha-tocopherol soft gels (200 IU three times daily), while the controls (n = 24) consumed the identical placebo soft gels for 10 weeks. At the baseline and end of the study, 7 ml pre-dialysis blood samples were taken from all participants to measure their serum concentrations of ICAM-1, VCAM-1, IL-6, and hs-CRP. RESULTS Alpha-tocopherol supplementation reduced the serum levels of ICAM-1 and VCAM-1 significantly (-140.67 ± 57.25 ng/ml vs. -15.97 ± 79.19 ng/ml, P = 0.001 for ICAM-1 and --6.79 ± 4.76 ng/ml vs. 1.02 ± 3.22 ng/ml, P = 0.019 for VCAM-1). However, no significant difference was observed between the two groups regarding the serum levels of hs-CRP (-0.15 ± 0.19 mg/l vs. 0.02 ± 0.12 mg/l; P = 0.32) and IL-6 (-0.03 ± 0.1 pg/ml vs. - 0.06 ± 0.11 pg/ml; P = 0.65). CONCLUSIONS Our results showed that 10 weeks of supplementation with 600 IU alpha-tocopherol improved ICAM-1 and VCAM-1 levels, but did not have any effect on the serum concentration of IL-6 and hs-CRP in hemodialysis patients. Further studies are required to confirm these findings.
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6.
Hydrogen sulfide reduces the activity of human endothelial cells.
Grambow, E, Klee, G, Xie, W, Schafmayer, C, Vollmar, B
Clinical hemorheology and microcirculation. 2020;(4):513-523
Abstract
INTRODUCTION The volatile endogenous mediator hydrogen sulfide (H2S) is known to impair thrombus formation by affecting the activity of human platelets. Beside platelets and coagulation factors the endothelium is crucial during thrombogenesis. OBJECTIVE This study evaluates the effect of the H2S donor GYY4137 (GYY) on human umbilical vein endothelial cells (HUVECs) in vitro. METHODS Flow cytometry of resting, stimulated or GYY-treated and subsequently stimulated HUVECs was performed to analyse the expression of E-selectin, ICAM-1 and VCAM-1. To study a potential reversibility of the GYY action, E-selectin expression was further assessed on HUVECs that were stimulated 24 h after GYY exposure. A WST-1 assay was performed to study toxic effects of the H2S donor. By using the biotin switch assay, protein S-sulfhydration of GYY-exposed HUVECs was assessed. Further on, the effects of GYY on HUVEC migration and von Willebrand factor (vWF) secretion were assessed. RESULTS GYY treatment significantly reduced the expression of E-selectin and ICAM-1 but not of VCAM-1. When HUVECs were stimulated 24 h after GYY treatment, E-selectin expression was no longer affected. The WST-1 assay revealed no effects of GYY on endothelial cell viability. Furthermore, GYY impaired endothelial migration, reduced vWF secretion and increased protein S-sulfhydration. CONCLUSIONS Summarizing, GYY dose dependently and reversibly reduces the activity of endothelial cells.
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7.
Endothelial dysfunction in neuroprogressive disorders-causes and suggested treatments.
Morris, G, Puri, BK, Olive, L, Carvalho, A, Berk, M, Walder, K, Gustad, LT, Maes, M
BMC medicine. 2020;(1):305
Abstract
BACKGROUND Potential routes whereby systemic inflammation, oxidative stress and mitochondrial dysfunction may drive the development of endothelial dysfunction and atherosclerosis, even in an environment of low cholesterol, are examined. MAIN TEXT Key molecular players involved in the regulation of endothelial cell function are described, including PECAM-1, VE-cadherin, VEGFRs, SFK, Rho GEF TRIO, RAC-1, ITAM, SHP-2, MAPK/ERK, STAT-3, NF-κB, PI3K/AKT, eNOS, nitric oxide, miRNAs, KLF-4 and KLF-2. The key roles of platelet activation, xanthene oxidase and myeloperoxidase in the genesis of endothelial cell dysfunction and activation are detailed. The following roles of circulating reactive oxygen species (ROS), reactive nitrogen species and pro-inflammatory cytokines in the development of endothelial cell dysfunction are then described: paracrine signalling by circulating hydrogen peroxide, inhibition of eNOS and increased levels of mitochondrial ROS, including compromised mitochondrial dynamics, loss of calcium ion homeostasis and inactivation of SIRT-1-mediated signalling pathways. Next, loss of cellular redox homeostasis is considered, including further aspects of the roles of hydrogen peroxide signalling, the pathological consequences of elevated NF-κB, compromised S-nitrosylation and the development of hypernitrosylation and increased transcription of atherogenic miRNAs. These molecular aspects are then applied to neuroprogressive disorders by considering the following potential generators of endothelial dysfunction and activation in major depressive disorder, bipolar disorder and schizophrenia: NF-κB; platelet activation; atherogenic miRs; myeloperoxidase; xanthene oxidase and uric acid; and inflammation, oxidative stress, nitrosative stress and mitochondrial dysfunction. CONCLUSIONS Finally, on the basis of the above molecular mechanisms, details are given of potential treatment options for mitigating endothelial cell dysfunction and activation in neuroprogressive disorders.
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8.
Effects of pomegranate peel extract and vitamin E on the inflammatory status and endothelial function in hemodialysis patients: a randomized controlled clinical trial.
Jafari, T, Fallah, AA, Reyhanian, A, Sarmast, E
Food & function. 2020;(9):7987-7993
Abstract
Inflammation and endothelial dysfunction are major problems in hemodialysis (HD) patients. This study assessed the effects of an 8 week administration of pomegranate peel extract (PPE) and vitamin E (Vit E) alone or in combination on the biomarkers of inflammation, including C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), and the biomarkers of endothelial function, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and P-selectin, in HD patients. In a randomized, double-blind, parallel, placebo-controlled trial, 100 HD patients were randomly divided into 4 equal groups: (a) PPE + Vit E, received 2 pomegranate tablets (each tablet contained 225 mg PPE, equal to 90 mg ellagic acid) + 1 Vit E soft gel (400 IU) daily, (b) PPE, received 2 pomegranate tablets + 1 Vit E placebo soft gel daily, (c) Vit E, received 1 Vit E soft gel + 2 pomegranate placebo tablets daily, and (d) placebo, received 2 pomegranate placebo tablets + 1 Vit E placebo soft gel daily. For group allocation, a stratified block randomization procedure based on sex, age, and HD duration was used. Each intervention product and its placebo had identical shape, color, size, and packaging. Consumption of PPE + Vit E significantly reduced the serum CRP level (mean change: -7.12 ± 4.59 mg l-1, P < 0.001) compared to other groups, while reduced levels of IL-6 (mean change: -2.19 ± 2.33 pg ml-1, P < 0.001), TNF-α (mean change: -2.41 ± 3.21 pg ml-1, P = 0.008), ICAM-1 (mean change: -64.2 ± 111.0 ng ml-1, P = 0.017), and VCAM-1 (mean change: -117.7 ± 177.1 ng ml-1, P = 0.002) were observed compared to the control. There was no significant difference in the P-selectin level among the groups. Consumption of PPE or Vit E alone significantly reduced the CRP level (mean change for PPE: -3.58 ± 5.41 mg l-1, P < 0.001; mean change for Vit E: -3.25 ± 8.29 mg l-1, P = 0.002) compared to the control. As a result, consumption of PPE in combination with Vit E enhanced the inflammatory status and endothelial function in HD patients.
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9.
Endothelial Progenitors in the Tumor Microenvironment.
Testa, U, Pelosi, E, Castelli, G
Advances in experimental medicine and biology. 2020;:85-115
Abstract
Tumor vascularization refers to the formation of new blood vessels within a tumor and is considered one of the hallmarks of cancer. Tumor vessels supply the tumor with oxygen and nutrients, required to sustain tumor growth and progression, and provide a gateway for tumor metastasis through the blood or lymphatic vasculature. Blood vessels display an angiocrine capacity of supporting the survival and proliferation of tumor cells through the production of growth factors and cytokines. Although tumor vasculature plays an essential role in sustaining tumor growth, it represents at the same time an essential way to deliver drugs and immune cells to the tumor. However, tumor vasculature exhibits many morphological and functional abnormalities, thus resulting in the formation of hypoxic areas within tumors, believed to represent a mechanism to maintain tumor cells in an invasive state.Tumors are vascularized through a variety of modalities, mainly represented by angiogenesis, where VEGF and other members of the VEGF family play a key role. This has represented the basis for the development of anti-VEGF blocking agents and their use in cancer therapy: however, these agents failed to induce significant therapeutic effects.Much less is known about the cellular origin of vessel network in tumors. Various cell types may contribute to tumor vasculature in different tumors or in the same tumor, such as mature endothelial cells, endothelial progenitor cells (EPCs), or the same tumor cells through a process of transdifferentiation. Early studies have suggested a role for bone marrow-derived EPCs; these cells do not are true EPCs but myeloid progenitors differentiating into monocytic cells, exerting a proangiogenic effect through a paracrine mechanism. More recent studies have shown the existence of tissue-resident endothelial vascular progenitors (EVPs) present at the level of vessel endothelium and their possible involvement as cells of origin of tumor vasculature.
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10.
Signalling, Metabolic Pathways and Iron Homeostasis in Endothelial Cells in Health, Atherosclerosis and Alzheimer's Disease.
Bosseboeuf, E, Raimondi, C
Cells. 2020;(9)
Abstract
Endothelial cells drive the formation of new blood vessels in physiological and pathological contexts such as embryonic development, wound healing, cancer and ocular diseases. Once formed, all vessels of the vasculature system present an endothelial monolayer (the endothelium), lining the luminal wall of the vessels, that regulates gas and nutrient exchange between the circulating blood and tissues, contributing to maintaining tissue and vascular homeostasis. To perform their functions, endothelial cells integrate signalling pathways promoted by growth factors, cytokines, extracellular matrix components and signals from mechanosensory complexes sensing the blood flow. New evidence shows that endothelial cells rely on specific metabolic pathways for distinct cellular functions and that the integration of signalling and metabolic pathways regulates endothelial-dependent processes such as angiogenesis and vascular homeostasis. In this review, we provide an overview of endothelial functions and the recent advances in understanding the role of endothelial signalling and metabolism in physiological processes such as angiogenesis and vascular homeostasis and vascular diseases. Also, we focus on the signalling pathways promoted by the transmembrane protein Neuropilin-1 (NRP1) in endothelial cells, its recently discovered role in regulating mitochondrial function and iron homeostasis and the role of mitochondrial dysfunction and iron in atherosclerosis and neurodegenerative diseases.