scholarly journals Role of Endothelial Cell–Derived Angptl2 in Vascular Inflammation Leading to Endothelial Dysfunction and Atherosclerosis Progression

2014 ◽  
Vol 34 (4) ◽  
pp. 790-800 ◽  
Author(s):  
Eiji Horio ◽  
Tsuyoshi Kadomatsu ◽  
Keishi Miyata ◽  
Yasumichi Arai ◽  
Kentaro Hosokawa ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Molecular Mechanisms ◽  
Vascular Inflammation ◽  
Nuclear Factor Κb ◽  
Atherosclerosis Progression ◽  
Atheromatous Plaques

Objective— Cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression. Approach and Results— Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E–deficient mice ( ApoE −/− / Angptl2 −/− ) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely, ApoE −/− mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter ( ApoE −/− /Tie2- Angptl2 Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2- Angptl2 Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell–derived nitric oxide. Conversely, Angptl2 −/− mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis. Conclusions— Endothelial cell–derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.

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

2020 ◽  
Vol 21 (23) ◽  
pp. 9309
Author(s):  
Jessica Maiuolo ◽  
Rocco Mollace ◽  
Micaela Gliozzi ◽  
Vincenzo Musolino ◽  
Cristina Carresi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Blood Vessels ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Vascular Complications ◽  
Therapeutic Interventions ◽  
The Impact

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.

scholarly journals Inflammatory Mechanisms Contributing to Endothelial Dysfunction

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 781
Author(s):  
Panagiotis Theofilis ◽  
Marios Sagris ◽  
Evangelos Oikonomou ◽  
Alexios S. Antonopoulos ◽  
Gerasimos Siasos ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Inflammatory Mediators ◽  
Leukocyte Adhesion ◽  
Vascular Inflammation ◽  
Endothelial Activation ◽  
Nuclear Factor Κb ◽  
Cellular Adhesion ◽  
Cell Integrity ◽  
Atherosclerosis Progression

Maintenance of endothelial cell integrity is an important component of human health and disease since the endothelium can perform various functions including regulation of vascular tone, control of hemostasis and thrombosis, cellular adhesion, smooth muscle cell proliferation, and vascular inflammation. Endothelial dysfunction is encompassed by complex pathophysiology that is based on endothelial nitric oxide synthase uncoupling and endothelial activation following stimulation from various inflammatory mediators (molecular patterns, oxidized lipoproteins, cytokines). The downstream signaling via nuclear factor-κB leads to overexpression of adhesion molecules, selectins, and chemokines that facilitate leukocyte adhesion, rolling, and transmigration to the subendothelial space. Moreover, oscillatory shear stress leads to pro-inflammatory endothelial activation with increased monocyte adhesion and endothelial cell apoptosis, an effect that is dependent on multiple pathways and flow-sensitive microRNA regulation. Moreover, the role of neutrophil extracellular traps and NLRP3 inflammasome as inflammatory mechanisms contributing to endothelial dysfunction has recently been unveiled and is under further investigation. Consequently, and following their activation, injured endothelial cells release inflammatory mediators and enter a pro-thrombotic state through activation of coagulation pathways, downregulation of thrombomodulin, and an increase in platelet adhesion and aggregation owing to the action of von-Willebrand factor, ultimately promoting atherosclerosis progression.

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

2020 ◽  
Author(s):  
Jessica Maiuolo ◽  
Rocco Mollace ◽  
Micaela Gliozzi ◽  
Vincenzo Musolino ◽  
Cristina Carresi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Blood Vessels ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Vascular Complications ◽  
Therapeutic Interventions ◽  
The Impact

Abstract: 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 SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with ACE2 receptor located in 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 patients 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 to the interaction of SARS CoV-2 with 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.

Antibodies to kidney endothelial cells contribute to a “leaky” glomerular barrier in patients with chronic kidney diseases

2012 ◽  
Vol 302 (7) ◽  
pp. F884-F894 ◽  
Author(s):  
Nidia Maritza Hernandez ◽  
Anna Casselbrant ◽  
Meghnad Joshi ◽  
Bengt R. Johansson ◽  
Suchitra Sumitran-Holgersson
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Kidney Diseases ◽  
Clinical Importance ◽  
Human Kidney ◽  
Cell Permeability ◽  
Chronic Kidney Diseases ◽  
Esrd Patients

Anti-endothelial cell antibodies (AECA) have been reported to cause endothelial dysfunction, but their clinical importance for tissue-specific endothelial cells is not clear. We hypothesized that AECA reactive with human kidney endothelial cells (HKEC) may cause renal endothelial dysfunction in patients with chronic kidney diseases. We report that a higher fraction (56%) of end-stage renal disease (ESRD) patients than healthy controls (5%) have AECA reactive against kidney endothelial cells ( P <0.001). The presence of antibodies was associated with female gender ( P < 0.001), systolic hypertension ( P < 0.01), and elevated TNF-α ( P < 0.05). These antibodies markedly decrease expression of both adherens and tight junction proteins VE-cadherin, claudin-1, and zonula occludens-1 and provoked a rapid increase in cytosolic free Ca2+and rearrangement of actin filaments in HKEC compared with controls. This was followed by an enhancement in protein flux and phosphorylation of VE-cadherin, events associated with augmented endothelial cell permeability. Additionally, kidney biopsies from ESRD patients with AECA but not controls demonstrated a marked decrease in adherens and tight junctions in glomerular endothelium, confirming our in vitro data. In summary, our data demonstrate a causal link between AECA and their capacity to induce alterations in glomerular vascular permeability.

Abstract 116: Arterial Endothelial Cell Has Stronger Angiogenic Potential Compared To Venous Endothelial Cell Through Up-regulation Of Endogenous FGF2 And FGF5 Expression In 3D Microfluidic System

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Ha-Rim Seo ◽  
Hyo Eun Jeong ◽  
Hyung Joon Joo ◽  
Seung-Cheol Choi ◽  
Jong-Ho Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Molecular Mechanisms ◽  
Umbilical Vein ◽  
Assay System ◽  
Vascular Density ◽  
Angiogenic Potential ◽  
Angiogenesis Assay

Background: Human body contains many kinds of different type of endothelial cells (EC). However, cellular difference of their angiogenic potential has been hardly understood. We compared in vitro angiogenic potential between arterial EC and venous EC and investigated its underlying molecular mechanisms. Method: Used human aortic endothelial cells (HAEC) which was indicated from arterial EC and human umbilical vein endothelial cells (HUVEC) indicated from venous EC. To explore angiogenic potential in detail, we adopted a novel 3D microfluidic angiogenesis assay system, which closely mimic in vivo angiogenesis. Results: In 3D microfluidic angiogenesis assay system, HAEC demonstrated stronger angiogenic potential compared to HUVEC. HAEC maintained its profound angiogenic property under different biophysical conditions. In mRNA microarray sorted on up- regulated or down-regulated genes, HAEC demonstrated significantly higher expression of gastrulation brain homeobox 2 (GBX2), fibroblast grow factor 2 (FGF2), FGF5 and collagen 8a1. Angiogenesis-related protein assay revealed that HAEC has higher secretion of endogenous FGF2 than HUVEC. HAEC has only up-regulated FGF2 and FGF5 in this part of FGF family. Furthermore, FGF5 expression under vascular endothelial growth factor-A (VEGF-A) stimulation was higher in HAEC compared to HUVEC although VEGF-A augmented FGF5 expression in both HAEC and HUVEC. Those data suggested that FGF5 expression in both HAEC and HUVEC is partially dependent to VEGF-A stimulate. HUVEC and HAEC reduced vascular density after FGF2 and FGF5 siRNA treat. Conclusion: HAEC has stronger angiogenic potential than HUVEC through up-regulation of endogenous FGF2 and FGF5 expression

scholarly journals Diabetic Endothelial Cells Differentiated From Patient iPSCs Show Dysregulated Glycine Homeostasis and Senescence Associated Phenotypes

2021 ◽  
Vol 9 ◽  
Author(s):  
Liping Su ◽  
Xiaocen Kong ◽  
Sze Jie Loo ◽  
Yu Gao ◽  
Jean-Paul Kovalik ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Pluripotent Stem Cells ◽  
Molecular Mechanisms ◽  
Cell Transfer ◽  
Angiogenic Potential ◽  
Patients With Diabetes ◽  
Induced Pluripotent

Induced pluripotent stem cells derived cells (iPSCs) not only can be used for personalized cell transfer therapy, but also can be used for modeling diseases for drug screening and discovery in vitro. Although prior studies have characterized the function of rodent iPSCs derived endothelial cells (ECs) in diabetes or metabolic syndrome, feature phenotypes are largely unknown in hiPSC-ECs from patients with diabetes. Here, we used hiPSC lines from patients with type 2 diabetes mellitus (T2DM) and differentiated them into ECs (dia-hiPSC-ECs). We found that dia-hiPSC-ECs had disrupted glycine homeostasis, increased senescence, and impaired mitochondrial function and angiogenic potential as compared with healthy hiPSC-ECs. These signature phenotypes will be helpful to establish dia-hiPSC-ECs as models of endothelial dysfunction for understanding molecular mechanisms of disease and for identifying and testing new targets for the treatment of endothelial dysfunction in diabetes.

Abstract 66: The Role of the Viral Nef Protein as a Mediator of HIV-1--Induced Endothelial Dysfunction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Ting Wang
Keyword(s):  
Cardiovascular Disease ◽  
T Cells ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Binding Site ◽  
Cell Activation ◽  
Endothelial Activation ◽  
Endothelial Cell Activation ◽  
Hiv 1

With the prevalence of antiviral therapy in the developed world, many HIV-1-infected people die of diseases other than AIDS. One of the emerging major causes is cardiovascular disease, leading to the prediction that the majority of HIV-1 patients are expected to develop cardiovascular complications. Endothelial dysfunction is thought to be a key event in the development of cardiovascular diseases, particularly atherosclerosis. Assays testing the effect of HIV-1 on endothelial activation shows that direct contact with HIV-1 infected T cells enhance endothelial cell activation to a greater extent than HIV-1 alone, suggesting an intracellular HIV-1 protein is responsible for endothelial activation. The HIV-1 viral protein Nef, which is responsible for T cell activation and maintenance of high viral loads in vivo , has been shown to mediate its own transfer to bystander cells. We demonstrate here for the first time that Nef induces nanotube-like conduits connecting T cells and endothelial cells. We also show that Nef is transferred from T cells to endothelial cells via these nanotubes, and is necessary and sufficient for endothelial cell activation. Moreover, we show that SIV-infected macaques exhibit endothelial Nef expression in coronary arteries. Nef expression in endothelial cells causes endothelial apoptosis, ROS and MCP-1 production. Interestingly, a Nef SH3 binding site mutant abolishes Nef-induced apoptosis and ROS formation and reduces MCP-1 production in endothelial cells, suggesting that the Nef SH3 binding site is critical for Nef effects on endothelial cells. Nef induces apoptosis of endothelial cells through an NADPH oxidase- and ROS-dependent mechanism, while Nef-induced MCP-1 production is NF-kB dependent. Taken together, these data suggest that Nef can mediate its transfer from T cells to endothelial cells through nanotubes to enhance endothelial dysfunction.Thus, Nef is a promising new therapeutic target for reducing the risk for cardiovascular disease in the HIV-1 positive population.

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.

scholarly journals The Roles of HIV-1 Proteins and Antiretroviral Drug Therapy in HIV-1-Associated Endothelial Dysfunction

2008 ◽  
Vol 56 (5) ◽  
pp. 752-769 ◽  
Author(s):  
Erik R. Kline ◽  
Roy L. Sutliff
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Dysfunction ◽  
Highly Active Antiretroviral Therapy ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Opportunistic Infections ◽  
Antiretroviral Drugs ◽  
Hiv 1

Since the emergence of highly active antiretroviral therapy (HAART), human immunodeficiency virus-1 (HIV-1)-infected patients have demonstrated dramatic decreases in viral burden and opportunistic infections, and an overall increase in life expectancy. Despite these positive HAART-associated outcomes, it has become increasingly clear that HIV-1 patients have an enhanced risk of developing cardiovascular disease over time. Clinical studies are instrumental in our understanding of vascular dysfunction in the context of HIV-1 infection. However, most clinical studies often do not distinguish whether HIV-1 proteins, HAART, or a combination of these 2 factors cause cardiovascular complications. This review seeks to address the roles of both HIV-1 proteins and antiretroviral drugs in the development of endothelial dysfunction because endothelial dysfunction is the hallmark initial step of many cardiovascular diseases. We analyze recentin vitroandin vivostudies examining endothelial toxicity in response to HIV-1 proteins or in response to the various classes of antiretroviral drugs. Furthermore, we discuss the multiple mechanisms by which HIV-1 proteins and HAART injure the vascular endothelium in HIV-1 patients. By understanding the molecular mechanisms of HIV-1 protein- and antiretroviral-induced cardiovascular disease, we may ultimately improve the quality of life of HIV-1 patients through better drug design and the discovery of new pharmacological targets.

C1q/TNF–Related Protein-3 attenuates endothelial dysfunction in diabetic retinopathy via the Nitric Oxide signaling pathway

2020 ◽  
Author(s):  
Zheyi Yan ◽  
Xiaoming Cao ◽  
Chunfang Wang ◽  
Sha Liu ◽  
Lu Gan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Cell Death ◽  
Diabetic Retinopathy ◽  
Endothelial Dysfunction ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Related Protein

Abstract Background Diabetic retinopathy (DR) is a severe microvasculature complication of diabetes. Restoration of dysfunctional endothelial cells represents a promising approach to treatment of DR. It has been demonstrated that a number of CTRP (C1q/tumor necrosis factor-related protein) members improves vascular endothelial function of the aortic vasculature. However, the role of CTRPs in the treatment of DR remains largely unresolved. Therefore, the aim of this study was to determine whether members of the CTRP family improve diabetes-induced endothelial dysfunction of retinal vasculature, thus exhibiting a protective effect against diabetic injury of retina. Methods The vasoactivity of currently identified murine CTRP family members was assessed in vascular rings and the underlying molecular mechanisms elucidated in human retinal microvascular endothelial cells. We then mimicked diabetic retinopathy both in vitro and in vivo, after which they were treated with CTRP3, and the vasoactivity, apoptotic cell death and vascular leakage in the retina were evaluated. Discovery-drive approaches followed by cause-effect analysis were used to uncover the molecular mechanisms of CTRP3. Results Our results demonstrate that CTRP3, CTRP5, and CTRP9 exert vasorelaxant effects on macro- and micro-vessels, with CTRP3 being the most potent in micro-vessels. The effects of CTRP3 were found to be endothelium-dependent via the AdipoR1/AMPK/eNOS/Nitric Oxide (NO) pathway. In in vitro microvascular reactivity studies, CTRP3 successfully improved high glucose/high lipid-induced impairment of endothelium-dependent vasodilatation. Blockade of either AMPK or eNOS completely abolished the previously observed effects of CTRP3. In addition, in the murine diabetic retinopathy model, CTRP3 treatment increased endothelium-dependent relaxation and NO levels in microvessels, and inhibited apoptotic cell death and vascular leakage in the retina. Finally,blockade of NO synthesis completely abolished the effects of CTRP3 that had been measured previously. Conclusion Taken together, our findings reveal that the AdipoR1/AMPK/eNOS/NO signaling pathway, through which CTRP3 reverses endothelial dysfunction of the microvasculature by normalization of impaired vasodilatation, represents a novel intervention effective against diabetic injury of retina.

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