scholarly journals Endothelial dysfunction in neuroprogressive disorders—causes and suggested treatments

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Gerwyn Morris ◽  
Basant K. Puri ◽  
Lisa Olive ◽  
Andre Carvalho ◽  
Michael Berk ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Mitochondrial Dysfunction ◽  
Platelet Activation ◽  
Endothelial Cell Dysfunction ◽  
Endothelial Cell Function ◽  
Paracrine Signalling ◽  
Cell Dysfunction

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.

scholarly journals Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia

2017 ◽  
Vol 232 (1) ◽  
pp. R27-R44 ◽  
Author(s):  
D S Boeldt ◽  
I M Bird
Keyword(s):  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Cell Function ◽  
Endothelial Cell Dysfunction ◽  
Hypertensive Disorders Of Pregnancy ◽  
Endothelial Cell Function ◽  
Vascular Adaptation ◽  
Cell Dysfunction ◽  
Maternal Adaptation ◽  
Flow Through

Maternal vascular adaptation to pregnancy is critically important to expand the capacity for blood flow through the uteroplacental unit to meet the needs of the developing fetus. Failure of the maternal vasculature to properly adapt can result in hypertensive disorders of pregnancy such as preeclampsia (PE). Herein, we review the endocrinology of maternal adaptation to pregnancy and contrast this with that of PE. Our focus is specifically on those hormones that directly influence endothelial cell function and dysfunction, as endothelial cell dysfunction is a hallmark of PE. A variety of growth factors and cytokines are present in normal vascular adaptation to pregnancy. However, they have also been shown to be circulating at abnormal levels in PE pregnancies. Many of these factors promote endothelial dysfunction when present at abnormal levels by acutely inhibiting key Ca2+ signaling events and chronically promoting the breakdown of endothelial cell–cell contacts. Increasingly, our understanding of how the contributions of the placenta, immune cells, and the endothelium itself promote the endocrine milieu of PE is becoming clearer. We then describe in detail how the complex endocrine environment of PE affects endothelial cell function, why this has contributed to the difficulty in fully understanding and treating this disorder, and how a focus on signaling convergence points of many hormones may be a more successful treatment strategy.

scholarly journals Methylglyoxal triggers human aortic endothelial cell dysfunction via modulation of the KATP/MAPK pathway

2019 ◽  
Vol 317 (1) ◽  
pp. C68-C81 ◽  
Author(s):  
Yihan Wang ◽  
Leo M. Hall ◽  
Marisa Kujawa ◽  
Hainan Li ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Network Formation ◽  
Cell Function ◽  
Mapk Pathway ◽  
Endothelial Cell Dysfunction ◽  
Endothelial Cell Function ◽  
Cell Dysfunction ◽  
Type 2 Diabetic

Endothelial dysfunction is a key risk factor in diabetes-related multiorgan damage. Methylglyoxal (MGO), a highly reactive dicarbonyl generated primarily as a by-product of glycolysis, is increased in both type 1 and type 2 diabetic patients. MGO can rapidly bind with proteins, nucleic acids, and lipids, resulting in structural and functional changes. MGO can also form advanced glycation end products (AGEs). How MGO causes endothelial cell dysfunction, however, is not clear. Human aortic endothelial cells (HAECs) from healthy (H-HAECs) and type 2 diabetic (D-HAECs) donors were cultured in endothelial growth medium (EGM-2). D-HAECs demonstrated impaired network formation (on Matrigel) and proliferation (MTT assay), as well as increased apoptosis (caspase-3/7 activity and TUNEL staining), compared with H-HAECs. High glucose (25 mM) or AGEs (200 ng/ml) did not induce such immediate, detrimental effects as MGO (10 µM). H-HAECs were treated with MGO (10 µM) for 24 h with or without the ATP-sensitive potassium (KATP) channel antagonist glibenclamide (1 µM). MGO significantly impaired H-HAEC network formation and proliferation and induced cell apoptosis, which was reversed by glibenclamide. Furthermore, siRNA against the KATP channel protein Kir6.1 significantly inhibited endothelial cell function at basal status but rescued impaired endothelial cell function upon MGO exposure. Meanwhile, activation of MAPK pathways p38 kinase, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) (determined by Western blot analyses of their phosphorylated forms, p-JNK, p-p38, and p-ERK) in D-HAECs were significantly enhanced compared with those in H-HAECs. MGO exposure enhanced the activation of all three MAPK pathways in H-HAECs, whereas glibenclamide reversed the activation of p-stress-activated protein kinase/JNK induced by MGO. Glyoxalase-1 (GLO1) is the endogenous MGO-detoxifying enzyme. In healthy mice that received an inhibitor of GLO1, MGO deposition in aortic wall was enhanced and endothelial cell sprouting from isolated aortic segment was significantly inhibited. Our data suggest that MGO triggers endothelial cell dysfunction by activating the JNK/p38 MAPK pathway. This effect arises partly through activation of KATP channels. By understanding how MGO induces endothelial dysfunction, our study may provide useful information for developing MGO-targeted interventions to treat vascular disorders in diabetes.

scholarly journals Linking In Vitro Models of Endothelial Dysfunction with Cell Senescence

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1323
Author(s):  
Francisco R. Jimenez Trinidad ◽  
Marta Arrieta Ruiz ◽  
Núria Solanes Batlló ◽  
Àngela Vea Badenes ◽  
Joaquim Bobi Gibert ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Umbilical Vein ◽  
In Vitro Models ◽  
Endothelial Cell Dysfunction ◽  
Gene Markers ◽  
Cell Dysfunction ◽  
Cellular Models

Endothelial cell dysfunction is the principal cause of several cardiovascular diseases that are increasing in prevalence, healthcare costs, and mortality. Developing a standardized, representative in vitro model of endothelial cell dysfunction is fundamental to a greater understanding of the pathophysiology, and to aiding the development of novel pharmacological therapies. We subjected human umbilical vein endothelial cells (HUVECs) to different periods of nutrient deprivation or increasing doses of H2O2 to represent starvation or elevated oxidative stress, respectively, to investigate changes in cellular function. Both in vitro cellular models of endothelial cell dysfunction-associated senescence developed in this study, starvation and oxidative stress, were validated by markers of cellular senescence (increase in β-galactosidase activity, and changes in senescence gene markers SIRT1 and P21) and endothelial dysfunction as denoted by reductions in angiogenic and migratory capabilities. HUVECs showed a significant H2O2 concentration-dependent reduction in cell viability (p < 0.0001), and a significant increase in oxidative stress (p < 0.0001). Furthermore, HUVECs subjected to 96 h of starvation, or exposed to concentrations of H2O2 of 400 to 1000 μM resulted in impaired angiogenic and migratory potentials. These models will enable improved physiological studies of endothelial cell dysfunction, and the rapid testing of cellular efficacy and toxicity of future novel therapeutic compounds.

scholarly journals Endoplasmic Reticulum Stress: A Critical Molecular Driver of Endothelial Dysfunction and Cardiovascular Disturbances Associated with Diabetes

2019 ◽  
Vol 20 (7) ◽  
pp. 1658 ◽  
Author(s):  
Hatem Maamoun ◽  
Shahenda Abdelsalam ◽  
Asad Zeidan ◽  
Hesham Korashy ◽  
Abdelali Agouni
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Endoplasmic Reticulum ◽  
Endothelial Cell ◽  
Er Stress ◽  
Cardiovascular Complications ◽  
Endothelial Cell Dysfunction ◽  
Cell Dysfunction ◽  
Obesity And Diabetes

Physical inactivity and sedentary lifestyle contribute to the widespread epidemic of obesity among both adults and children leading to rising cases of diabetes. Cardiovascular disease complications associated with obesity and diabetes are closely linked to insulin resistance and its complex implications on vascular cells particularly endothelial cells. Endoplasmic reticulum (ER) stress is activated following disruption in post-translational protein folding and maturation within the ER in metabolic conditions characterized by heavy demand on protein synthesis, such as obesity and diabetes. ER stress has gained much interest as a key bridging and converging molecular link between insulin resistance, oxidative stress, and endothelial cell dysfunction and, hence, represents an interesting drug target for diabetes and its cardiovascular complications. We reviewed here the role of ER stress in endothelial cell dysfunction, the primary step in the onset of atherosclerosis and cardiovascular disease. We specifically focused on the contribution of oxidative stress, insulin resistance, endothelial cell death, and cellular inflammation caused by ER stress in endothelial cell dysfunction and the process of atherogenesis.

Dissociation of endothelial cell dysfunction and blood pressure in SHR

1995 ◽  
Vol 269 (1) ◽  
pp. H189-H194 ◽  
Author(s):  
B. Tesfamariam ◽  
M. L. Ogletree
Keyword(s):  
Blood Pressure ◽  
Endothelial Cell ◽  
Cell Function ◽  
Receptor Activation ◽  
Endothelial Cell Dysfunction ◽  
Endothelial Cell Function ◽  
Cell Dysfunction ◽  
Tp Receptor ◽  
Wistar Kyoto ◽  
Endothelium Dependent Relaxation

This study was designed to examine the impairment of endothelium-dependent relaxation in spontaneously hypertensive rats (SHR), to determine whether endothelial cell function is normalized by in vivo treatment with a thromboxane A2-prostaglandin endoperoxide (TP)-receptor blocker, and to establish whether endothelial dysfunction contributes to the elevated blood pressure. In isolated aortic rings from SHR, endothelium-dependent relaxations caused by acetylcholine, adenosine diphosphate, and alpha-thrombin were markedly impaired compared with those from Wistar-Kyoto (WKY) normotensive rats. Arachidonic acid-induced contractions were significantly enhanced in aorta from SHR. In contrast, relaxations caused by direct smooth muscle vasodilators, nitroprusside and cromakalim, and contractions caused by U-46619 were not different between SHR and WKY rats. Treatment of SHR with the oral TP-receptor antagonist, ifetroban, at 20 and 50 mg.kg-1.day-1 fully restored endothelium-dependent relaxation toward normal. However, ifetroban produced no effect on blood pressure in SHR. In vitro incubation of aortic rings from SHR with ifetroban also normalized relaxations to acetylcholine but had no effect in aorta from WKY. In contrast, the thromboxane A synthase inhibitor, dazoxiben, only partially improved abnormal acetylcholine-induced relaxations in aorta from SHR. The results demonstrate that endothelial cell dysfunction in hypertension can be restored to normal by selective TP-receptor blockade. Furthermore, endothelial cell dysfunction and TP-receptor activation may not significantly contribute to elevated systemic blood pressure in SHR.

scholarly journals Corneal endothelial cell dysfunction: etiologies and management

2018 ◽  
Vol 10 ◽  
pp. 251584141881580 ◽  
Author(s):  
Sepehr Feizi
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Corneal Endothelial Cell ◽  
Endothelial Cell Dysfunction ◽  
Endothelial Keratoplasty ◽  
Corneal Endothelial Cells ◽  
Cell Dysfunction ◽  
Corneal Endothelial Dysfunction

A transparent cornea is essential for the formation of a clear image on the retina. The human cornea is arranged into well-organized layers, and each layer plays a significant role in maintaining the transparency and viability of the tissue. The endothelium has both barrier and pump functions, which are important for the maintenance of corneal clarity. Many etiologies, including Fuchs’ endothelial corneal dystrophy, surgical trauma, and congenital hereditary endothelial dystrophy, lead to endothelial cell dysfunction. The main treatment for corneal decompensation is replacement of the abnormal corneal layers with normal donor tissue. Nowadays, the trend is to perform selective endothelial keratoplasty, including Descemet stripping automated endothelial keratoplasty and Descemet’s membrane endothelial keratoplasty, to manage corneal endothelial dysfunction. This selective approach has several advantages over penetrating keratoplasty, including rapid recovery of visual acuity, less likelihood of graft rejection, and better patient satisfaction. However, the global limitation in the supply of donor corneas is becoming an increasing challenge, necessitating alternatives to reduce this demand. Consequently, in vitro expansion of human corneal endothelial cells is evolving as a sustainable choice. This method is intended to prepare corneal endothelial cells in vitro that can be transferred to the eye. Herein, we describe the etiologies and manifestations of human corneal endothelial cell dysfunction. We also summarize the available options for as well as recent developments in the management of corneal endothelial dysfunction.

Early hydrogen peroxide-induced pulmonary endothelial cell dysfunction: Detection and prevention

1994 ◽  
Vol 22 (1) ◽  
pp. 157-162 ◽  
Author(s):  
Philippe Jolliet ◽  
Barbara Polla ◽  
Alfred Donath ◽  
Daniel Slosman
Keyword(s):  
Hydrogen Peroxide ◽  
Endothelial Cell ◽  
Endothelial Cell Dysfunction ◽  
Cell Dysfunction

Increased Erythrocyte Rigidity Is Sufficient to Cause Endothelial Dysfunction in Sickle Cell Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 818-818 ◽  
Author(s):  
Robert Mannino ◽  
David R Myers ◽  
Yumiko Sakurai ◽  
Russell E. Ware ◽  
Gilda Barabino ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Adhesion Molecule ◽  
Endothelial Cell Dysfunction ◽  
Cell Disease ◽  
Cell Dysfunction ◽  
Sickle Erythrocytes

Abstract Abstract 818 Endothelial dysfunction is a major component of sickle cell disease (SCD) pathophysiology. Interestingly, previous cardiovascular research has definitively shown that endothelial cells biologically respond to mechanical forces and aberrations in these forces cause endothelial dysfunction via pro-inflammatory pathways that are also involved in SCD. While endothelial dysfunction in SCD has been well characterized biologically, little research has focused on the direct biophysical effects of SCD blood on endothelium. As endothelial cells are in constant contact with flowing “stiffened” sickle erythrocytes, we propose that the direct mechanical interactions between the physically altered sickle erythrocytes and endothelial cells are an additional cause of endothelial dysfunction in SCD (Figure 1A). Endothelial dysfunction in SCD is thought to be caused by the downstream effects of vaso-occlusion and/or hemolysis. Our laboratory has recently developed and published a description of an in vitro microvasculature model comprised of endothelial cells that are cultured throughout the entire 3D inner surface of a microfluidic system designed for investigating cellular interactions in hematologic diseases (Tsai, et al, JCI, 2012), (Figure 1B-D). This microvasculature-on-a-chip recapitulates an ensemble of physiological processes and biophysical properties, including adhesion molecule expression, blood cell-endothelial cell interactions, cell deformability, cell size/shape, microvascular geometry, hemodynamics, and oxygen levels (Myers et al. JoVE, 2012), all of which may contribute to endothelial dysfunction in SCD. We hypothesize that the mechanical interactions between sickle erythrocytes and endothelial cells alone are sufficientto cause endothelial dysfunction in our microvasculature-on-a-chip. To test our hypothesis, we flowed different suspensions of healthy red blood cells (RBCs), and stiffened RBCs, through our microvasculature on a chip cultured with HUVECs. We suspended fresh human RBCs in media at a low hematocrit recapitulating the anemic conditions typically seen in SCD patients as a control. The experimental conditions used the same solution as the control, but also contained glutaraldehyde-stiffened RBCs, which are of the same stiffness as irreversibly sickled cells (ISCs), at approximately the same concentrations as ISCs in SCD patients. The stiffened RBC suspension was washed multiple times to eliminate all traces of glutaraldehyde and to ensure that any endothelial cell dysfunction in our system was due to mechanical effects between the endothelium and RBCs. After 4 hours of perfusion, the number of occlusions in our microsystem was counted and the cells were fixed and stained for Vascular Cell Adhesion Molecule 1 (VCAM-1). VCAM-1 been shown to be a marker of endothelial cell dysfunction and is a biomarker for severe vasculopathy in SCD (Dworkis, Am J Hematol, 2011). Immunofluorescence staining in our microsystem confirmed that VCAM1 is upregulated (Figure 2) in HUVECs when exposed to flowing stiffened RBCs compared to control RBCs. VCAM-1 upregulation appears to be diffuse throughout the length of the device. After experimentation, endothelial cells in our system can be isolated for further RT-PCR or microarray analysis. As such, ongoing work involves investigating and quantifying the expression of other pro-inflammatory molecules to elucidate the underlying mechanisms of this biomechanical process involving RBCs and endothelial cells. Additional experiments complementary experiments using endothelial cells from other anatomic areas, SCD patient samples, and murine SCD models are also underway. Our data indicates that purely physical interactions between endothelial cells and stiffened RBCs are sufficient to cause some degree of endothelial dysfunction, even in the absence of vaso-occlusion, ischemia, or oxidative stress due to hemolysis. As sickle RBCs and ISCs are constantly circulating in the blood of SCD patients, our results have profound implications for SCD pathophysiology and may help explain why SCD patients develop chronic diffuse vasculopathy over time. Disclosures: No relevant conflicts of interest to declare.

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