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Biomedicines
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Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches
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Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 100737

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Byeong Hwa Jeon

E-Mail Website
Guest Editor
Department of Physiology, Chungnam National University, Daejeon, Republic of Korea
Interests: reactive oxygen species; vascular inflammation; endothelial dysfunction; biomaterials; tumor microenvironments
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Special Issue, “Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches”, will focus on the pathophysiology of endothelial dysfunction, new biomarkers for endothelial dysfunction related to cardiovascular disorders or tumors, and novel therapeutic approaches for endothelial dysfunctions.

Vascular endothelium is an active tissue and plays a crucial role in the maintenance of vascular homeostasis. The chronic exposure of risk factors, such as hypertension, high cholesterolemia, or oxidative stress, induces endothelial dysfunctions, and results in a loss of endothelial integrity, smooth muscle cell proliferation, and macrophage recruitment.

The pathophysiology of endothelial dysfunction (ED) is complex, and multi-factorial factors are involved, such as oxidative stress or chronic inflammation. The primary prevention of cardiovascular risk factors and endothelial dysfunctions, as well as the early detection or molecular imaging techniques for endothelial dysfunction help to prevent the development of cardiovascular disorders. Novel therapeutic approaches or drug delivery systems for endothelial dysfunctions have had a promising beneficial effect in preclinical or clinical levels, by  affecting the progression of atherosclerotic changes, tumor angiogenesis, and host–immune reaction near tumor environments.

This Special Issue is open for basic- to clinical-research, or a multi-disciplinary approach, and will also cover original articles and reviews on the following topics:

  • The target molecule or pathophysiology
  • The primary prevention of cardiovascular risk factors
  • Early detection or molecular imaging techniques
  • New therapeutic approaches including biomaterials
  • Drug delivery systems
  • Immunology and tumor environments

Dr. Byeong Hwa Jeon
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • endothelial dysfunction
  • reactive oxygen species and lipid peroxidation
  • atherosclerosis
  • adipose tissues and obesity
  • hypertension
  • hypercholesterolemia
  • vascular inflammation
  • tumor microenvironment
  • new biomarker or pathophysiology
  • novel therapeutic approach and pharmaceuticals

Related Special Issues

Published Papers (20 papers)

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Editorial

Jump to: Research, Review

3 pages, 178 KiB  
Editorial
Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches
by Byeong Hwa Jeon
Biomedicines 2021, 9(11), 1571; https://doi.org/10.3390/biomedicines9111571 - 29 Oct 2021
Cited by 3 | Viewed by 1311
Abstract
The vascular endothelium is an active tissue that plays a crucial role in the maintenance of vascular homeostasis [...] Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)

Research

Jump to: Editorial, Review

16 pages, 2720 KiB  
Article
An Atherogenic Diet Disturbs Aquaporin 5 Expression in Liver and Adipocyte Tissues of Apolipoprotein E-Deficient Mice: New Insights into an Old Model of Experimental Atherosclerosis
by Inês V. da Silva, Courtney A. Whalen, Floyd J. Mattie, Cristina Florindo, Neil K. Huang, Sandra G. Heil, Thomas Neuberger, A. Catharine Ross, Graça Soveral and Rita Castro
Biomedicines 2021, 9(2), 150; https://doi.org/10.3390/biomedicines9020150 - 04 Feb 2021
Cited by 6 | Viewed by 2207
Abstract
The dysfunction of vascular endothelial cells is profoundly implicated in the pathogenesis of atherosclerosis and cardiovascular disease, the global leading cause of death. Aquaporins (AQPs) are membrane channels that facilitate water and glycerol transport across cellular membranes recently implicated in the homeostasis of [...] Read more.
The dysfunction of vascular endothelial cells is profoundly implicated in the pathogenesis of atherosclerosis and cardiovascular disease, the global leading cause of death. Aquaporins (AQPs) are membrane channels that facilitate water and glycerol transport across cellular membranes recently implicated in the homeostasis of the cardiovascular system. Apolipoprotein-E deficient (apoE−/−) mice are a common model to study the progression of atherosclerosis. Nevertheless, the pattern of expression of AQPs in this atheroprone model is poorly characterized. In this study, apoE−/− mice were fed an atherogenic high-fat (HF) or a control diet. Plasma was collected at multiple time points to assess metabolic disturbances. At the endpoint, the aortic atherosclerotic burden was quantified using high field magnetic resonance imaging. Moreover, the transcriptional levels of several AQP isoforms were evaluated in the liver, white adipocyte tissue (WAT), and brown adipocyte tissue (BAT). The results revealed that HF-fed mice, when compared to controls, presented an exacerbated systemic inflammation and atherosclerotic phenotype, with no major differences in systemic methylation status, circulating amino acids, or plasma total glutathione. Moreover, an overexpression of the isoform AQP5 was detected in all studied tissues from HF-fed mice when compared to controls. These results suggest a novel role for AQP5 on diet-induced atherosclerosis that warrants further investigation. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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19 pages, 6321 KiB  
Article
The Inhibition of Prolyl Oligopeptidase as New Target to Counteract Chronic Venous Insufficiency: Findings in a Mouse Model
by Giovanna Casili, Marika Lanza, Sarah Adriana Scuderi, Salvatore Messina, Irene Paterniti, Michela Campolo and Emanuela Esposito
Biomedicines 2020, 8(12), 604; https://doi.org/10.3390/biomedicines8120604 - 13 Dec 2020
Cited by 10 | Viewed by 2214
Abstract
(1) Background: Chronic venous insufficiency (CVI) is a common disorder related to functional and morphological abnormalities of the venous system. Inflammatory processes and angiogenesis alterations greatly concur to the onset of varicose vein. KYP-2047 is a selective inhibitor of prolyl oligopeptidase (POP), a [...] Read more.
(1) Background: Chronic venous insufficiency (CVI) is a common disorder related to functional and morphological abnormalities of the venous system. Inflammatory processes and angiogenesis alterations greatly concur to the onset of varicose vein. KYP-2047 is a selective inhibitor of prolyl oligopeptidase (POP), a serine protease involved in the release of pro-angiogenic molecules. The aim of the present study is to evaluate the capacity of KYP-2047 to influence the angiogenic and inflammatory mechanisms involved in the pathophysiology of CVI. (2) Methods: An in vivo model of CVI-induced by saphene vein ligation (SVL) and a tissue block culture study were performed. Mice were subjected to SVL followed by KYP-2047 treatment (intraperitoneal, 10 mg/kg) for 7 days. Histological analysis, Masson’s trichrome, Van Gieson staining, and mast cells evaluation were performed. Release of cytokines, nitric oxide synthase production, TGF-beta, VEGF, α-smooth muscle actin, PREP, Endoglin, and IL-8 quantification were investigated. (3) Results: KYP-2047 treatment ameliorated the histological abnormalities of the venous wall, reduced the collagen increase and modulated elastin content, lowered cytokines levels and prevented mast degranulation. Moreover, a decreased expression of TGF-beta, eNOS, VEGF, α-smooth muscle actin, IL-8, and PREP was observed in in vivo study; also a reduction in VEGF and Endoglin expression was confirmed in tissue block culture study. (4) Conclusions: For the first time, this research, highlighting the importance of POP as new target for vascular disorders, revealed the therapeutic potential of KYP-2047 as a helpful treatment for the management of CVI. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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16 pages, 2052 KiB  
Article
Plasma APE1/Ref-1 Correlates with Atherosclerotic Inflammation in ApoE−/− Mice
by Yu Ran Lee, Hee Kyoung Joo, Eun-Ok Lee, Myoung Soo Park, Hyun Sil Cho, Sungmin Kim, Hao Jin, Jin-Ok Jeong, Cuk-Seong Kim and Byeong Hwa Jeon
Biomedicines 2020, 8(9), 366; https://doi.org/10.3390/biomedicines8090366 - 21 Sep 2020
Cited by 15 | Viewed by 3097
Abstract
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is involved in DNA base repair and reducing activity. However, the role of APE1/Ref-1 in atherosclerosis is unclear. Herein, we investigated the role of APE1/Ref-1 in atherosclerotic apolipoprotein E (ApoE−/−) mice fed with a Western-type diet. [...] Read more.
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is involved in DNA base repair and reducing activity. However, the role of APE1/Ref-1 in atherosclerosis is unclear. Herein, we investigated the role of APE1/Ref-1 in atherosclerotic apolipoprotein E (ApoE−/−) mice fed with a Western-type diet. We found that serologic APE1/Ref-1 was strongly correlated with vascular inflammation in these mice. Neutrophil/lymphocyte ratio (NLR), endothelial cell/macrophage activation, and atherosclerotic plaque formation, reflected by atherosclerotic inflammation, were increased in the ApoE−/− mice fed with a Western-type diet. APE1/Ref-1 expression was upregulated in aortic tissues of these mice, and was co-localized with cells positive for cluster of differentiation 31 (CD31) and galectin-3, suggesting endothelial cell/macrophage expression of APE1/Ref-1. Interestingly, APE1/Ref-1 plasma levels of ApoE−/− mice fed with a Western-type diet were significantly increased compared with those of the mice fed with normal diet (15.76 ± 3.19 ng/mL vs. 3.51 ± 0.50 ng/mL, p < 0.05), and were suppressed by atorvastatin administration. Correlation analysis showed high correlation between plasma APE1/Ref-1 levels and NLR, a marker of systemic inflammation. The cut-off value for APE1/Ref-1 for predicting atherosclerotic inflammation at 4.903 ng/mL showed sensitivity of 100% and specificity of 91%. We conclude that APE1/Ref-1 expression is upregulated in aortic endothelial cells/macrophages of atherosclerotic mice, and that plasma APE1/Ref-1 levels could predict atherosclerotic inflammation. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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Graphical abstract

12 pages, 4331 KiB  
Article
Novel Nargenicin A1 Analog Inhibits Angiogenesis by Downregulating the Endothelial VEGF/VEGFR2 Signaling and Tumoral HIF-1α/VEGF Pathway
by Jang Mi Han, Ye Seul Choi, Dipesh Dhakal, Jae Kyung Sohng and Hye Jin Jung
Biomedicines 2020, 8(8), 252; https://doi.org/10.3390/biomedicines8080252 - 29 Jul 2020
Cited by 10 | Viewed by 2200
Abstract
Targeting angiogenesis is an attractive strategy for the treatment of angiogenesis-related diseases, including cancer. We previously identified 23-demethyl 8,13-deoxynargenicin (compound 9) as a novel nargenicin A1 analog with potential anticancer activity. In this study, we investigated the antiangiogenic activity and mode of [...] Read more.
Targeting angiogenesis is an attractive strategy for the treatment of angiogenesis-related diseases, including cancer. We previously identified 23-demethyl 8,13-deoxynargenicin (compound 9) as a novel nargenicin A1 analog with potential anticancer activity. In this study, we investigated the antiangiogenic activity and mode of action of compound 9. This compound was found to effectively inhibit in vitro angiogenic characteristics, including the proliferation, invasion, capillary tube formation, and adhesion of human umbilical vein endothelial cells (HUVECs) stimulated by vascular endothelial growth factor (VEGF). Furthermore, compound 9 suppressed the neovascularization of the chorioallantoic membrane of growing chick embryos in vivo. Notably, the antiangiogenic properties of compound 9 were related to the downregulation of VEGF/VEGFR2-mediated downstream signaling pathways, as well as matrix metalloproteinase (MMP)-2 and MMP-9 expression in HUVECs. In addition, compound 9 was found to decrease the in vitro AGS gastric cancer cell-induced angiogenesis of HUVECs by blocking hypoxia-inducible factor-1α (HIF-1α) and VEGF expression in AGS cells. Collectively, our findings demonstrate for the first time that compound 9 is a promising antiangiogenic agent targeting both VEGF/VEGFR2 signaling in ECs and HIF-1α/VEGF pathway in tumor cells. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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9 pages, 430 KiB  
Article
Serum γ-Glutamyltransferase Concentration Predicts Endothelial Dysfunction in Naïve Hypertensive Patients
by Maria Perticone, Raffaele Maio, Benedetto Caroleo, Angela Sciacqua, Edoardo Suraci, Simona Gigliotti, Francesco Martino, Francesco Andreozzi, Giorgio Sesti and Francesco Perticone
Biomedicines 2020, 8(7), 207; https://doi.org/10.3390/biomedicines8070207 - 11 Jul 2020
Cited by 2 | Viewed by 2007
Abstract
Background: Serum gamma-glutamyltransferase (γ-GT) is recognized as a risk factor for cardiovascular diseases (CV). Traditional cardiovascular risk factors mediate endothelial dysfunction. Aim: to evaluate a possible correlation between serum γ-GT and endothelium-dependent vasodilation in naïve hypertensives. Methods: We enrolled 500 hypertensives. Endothelial function [...] Read more.
Background: Serum gamma-glutamyltransferase (γ-GT) is recognized as a risk factor for cardiovascular diseases (CV). Traditional cardiovascular risk factors mediate endothelial dysfunction. Aim: to evaluate a possible correlation between serum γ-GT and endothelium-dependent vasodilation in naïve hypertensives. Methods: We enrolled 500 hypertensives. Endothelial function was studied by strain-gauge plethysmography. Receiver operating characteristic (ROC) analysis was used to assess the predictive value of γ-GT and to identify the optimal cut-off value of the same variable for endothelial dysfunction. Results: At univariate linear analysis peak percent increase in acetylcholine (ACh)-stimulated vasodilation was inversely related to γ-GT (r = −0.587), alanine aminotransferase (ALT) (r = −0.559), aspartate aminotransferase (AST) (r = −0.464), age (r = −0.171), body mass index (BMI) (r = −0.152), and fasting glucose (r = −101). In the stepwise multivariate regression model, endothelium-dependent vasodilation was significantly related to γ-GT (β = −0.362), ALT (β = −0.297), AST (β = −0.217), estimated glomerular filtration rate (e-GFR) (β = 0.199), gender (β = 0.166), and smoking (β = −0.061). The ROC analysis demonstrated that the accuracy of γ-GT for identifying patients with endothelial dysfunction was 82.1%; the optimal γ-GT cut-off value for discriminating patients with this alteration was 27 UI/L. Conclusions: Serum γ-GT values, within the normal range, are significantly associated with endothelial dysfunction in hypertensives, and may be considered a biomarker of early vascular damage. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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11 pages, 1602 KiB  
Article
Aerobic Exercise Training Inhibits Neointimal Formation via Reduction of PCSK9 and LOX-1 in Atherosclerosis
by Wei Li, Heegeun Park, Erling Guo, Wooyeon Jo, Kyu Min Sim and Sang Ki Lee
Biomedicines 2020, 8(4), 92; https://doi.org/10.3390/biomedicines8040092 - 19 Apr 2020
Cited by 6 | Viewed by 2988
Abstract
The purpose of this study was to investigate whether aerobic exercise training inhibits atherosclerosis via the reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) expression in balloon-induced common carotid arteries of a high-fat-diet rats. Male SD (Sprague Dawley) rats fed an eight-weeks high-fat [...] Read more.
The purpose of this study was to investigate whether aerobic exercise training inhibits atherosclerosis via the reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) expression in balloon-induced common carotid arteries of a high-fat-diet rats. Male SD (Sprague Dawley) rats fed an eight-weeks high-fat diet were randomly divided into three groups; these were the sham-operated control (SC), the balloon-induced control (BIC) and the balloon-induced exercise (BIE). The aerobic exercise training groups were performed on a treadmill. The major findings were as follows: first, body weight gain was significantly decreased by aerobic exercise training compared to the BIC without change of energy intake. Second, neointimal formation was significantly inhibited by aerobic exercise training in the balloon-induced common carotid arteries of high-fat-diet rats compared to the BIC. Third, low-density lipoprotein (LDL) receptor (LDLr) expression was significantly increased by aerobic exercise training in the livers of the high-fat diet group compared to the BIC, but not the proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. Fourth, aerobic exercise training significantly decreased the expression of PCSK9, the lectin-like oxidized LDL receptor-1 (LOX-1), and vascular cell adhesion molecule-1 (VCAM-1) in balloon-induced common carotid arteries of high-fat-diet rats compared to the BIC. In conclusion, our results suggest that aerobic exercise training increases LDLr in the liver and inhibits neointimal formation via the reduction of PCSK9 and LOX-1 in balloon-induced common carotid arteries of high-fat-diet-induced rats. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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Review

Jump to: Editorial, Research

21 pages, 1944 KiB  
Review
Vascular Calcification in Chronic Kidney Disease: Diversity in the Vessel Wall
by Prabhatchandra Dube, Armelle DeRiso, Mitra Patel, Dhanushya Battepati, Bella Khatib-Shahidi, Himani Sharma, Rajesh Gupta, Deepak Malhotra, Lance Dworkin, Steven Haller and David Kennedy
Biomedicines 2021, 9(4), 404; https://doi.org/10.3390/biomedicines9040404 - 08 Apr 2021
Cited by 33 | Viewed by 8547
Abstract
Vascular calcification (VC) is one of the major causes of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). VC is a complex process expressing similarity to bone metabolism in onset and progression. VC in CKD is promoted by various factors [...] Read more.
Vascular calcification (VC) is one of the major causes of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). VC is a complex process expressing similarity to bone metabolism in onset and progression. VC in CKD is promoted by various factors not limited to hyperphosphatemia, Ca/Pi imbalance, uremic toxins, chronic inflammation, oxidative stress, and activation of multiple signaling pathways in different cell types, including vascular smooth muscle cells (VSMCs), macrophages, and endothelial cells. In the current review, we provide an in-depth analysis of the various kinds of VC, the clinical significance and available therapies, significant contributions from multiple cell types, and the associated cellular and molecular mechanisms for the VC process in the setting of CKD. Thus, we seek to highlight the key factors and cell types driving the pathology of VC in CKD in order to assist in the identification of preventative, diagnostic, and therapeutic strategies for patients burdened with this disease. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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24 pages, 1767 KiB  
Review
Experimental and Clinical Applications of Red and Near-Infrared Photobiomodulation on Endothelial Dysfunction: A Review
by Esteban Colombo, Antonio Signore, Stefano Aicardi, Angelina Zekiy, Anatoliy Utyuzh, Stefano Benedicenti and Andrea Amaroli
Biomedicines 2021, 9(3), 274; https://doi.org/10.3390/biomedicines9030274 - 09 Mar 2021
Cited by 30 | Viewed by 6260
Abstract
Background: Under physiological conditions, endothelial cells are the main regulator of arterial tone homeostasis and vascular growth, sensing and transducing signals between tissue and blood. Disease risk factors can lead to their unbalanced homeostasis, known as endothelial dysfunction. Red and near-infrared light can [...] Read more.
Background: Under physiological conditions, endothelial cells are the main regulator of arterial tone homeostasis and vascular growth, sensing and transducing signals between tissue and blood. Disease risk factors can lead to their unbalanced homeostasis, known as endothelial dysfunction. Red and near-infrared light can interact with animal cells and modulate their metabolism upon interaction with mitochondria’s cytochromes, which leads to increased oxygen consumption, ATP production and ROS, as well as to regulate NO release and intracellular Ca2+ concentration. This medical subject is known as photobiomodulation (PBM). We present a review of the literature on the in vitro and in vivo effects of PBM on endothelial dysfunction. Methods: A search strategy was developed consistent with the PRISMA statement. The PubMed, Scopus, Cochrane, and Scholar electronic databases were consulted to search for in vitro and in vivo studies. Results: Fifty out of >12,000 articles were selected. Conclusions: The PBM can modulate endothelial dysfunction, improving inflammation, angiogenesis, and vasodilatation. Among the studies, 808 nm and 18 J (0.2 W, 2.05 cm2) intracoronary irradiation can prevent restenosis as well as 645 nm and 20 J (0.25 W, 2 cm2) can stimulate angiogenesis. PBM can also support hypertension cure. However, more extensive randomised controlled trials are necessary. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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17 pages, 2186 KiB  
Review
Endothelial Cell Glucose Metabolism and Angiogenesis
by Wa Du, Lu Ren, Milton H. Hamblin and Yanbo Fan
Biomedicines 2021, 9(2), 147; https://doi.org/10.3390/biomedicines9020147 - 03 Feb 2021
Cited by 34 | Viewed by 5038
Abstract
Angiogenesis, a process of new blood vessel formation from the pre-existing vascular bed, is a critical event in various physiological and pathological settings. Over the last few years, the role of endothelial cell (EC) metabolism in angiogenesis has received considerable attention. Accumulating studies [...] Read more.
Angiogenesis, a process of new blood vessel formation from the pre-existing vascular bed, is a critical event in various physiological and pathological settings. Over the last few years, the role of endothelial cell (EC) metabolism in angiogenesis has received considerable attention. Accumulating studies suggest that ECs rely on aerobic glycolysis, rather than the oxidative phosphorylation pathway, to produce ATP during angiogenesis. To date, numerous critical regulators of glucose metabolism, fatty acid oxidation, and glutamine metabolism have been identified to modulate the EC angiogenic switch and pathological angiogenesis. The unique glycolytic feature of ECs is critical for cell proliferation, migration, and responses to environmental changes. In this review, we provide an overview of recent EC glucose metabolism studies, particularly glycolysis, in quiescent and angiogenic ECs. We also summarize and discuss potential therapeutic strategies that take advantage of EC metabolism. The elucidation of metabolic regulation and the precise underlying mechanisms could facilitate drug development targeting EC metabolism to treat angiogenesis-related diseases. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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Graphical abstract

23 pages, 2419 KiB  
Review
Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?
by Kondababu Kurakula, Valérie F. E. D. Smolders, Olga Tura-Ceide, J. Wouter Jukema, Paul H. A. Quax and Marie-José Goumans
Biomedicines 2021, 9(1), 57; https://doi.org/10.3390/biomedicines9010057 - 09 Jan 2021
Cited by 57 | Viewed by 9593
Abstract
Pulmonary arterial hypertension (PAH) is a rare, complex, and progressive disease that is characterized by the abnormal remodeling of the pulmonary arteries that leads to right ventricular failure and death. Although our understanding of the causes for abnormal vascular remodeling in PAH is [...] Read more.
Pulmonary arterial hypertension (PAH) is a rare, complex, and progressive disease that is characterized by the abnormal remodeling of the pulmonary arteries that leads to right ventricular failure and death. Although our understanding of the causes for abnormal vascular remodeling in PAH is limited, accumulating evidence indicates that endothelial cell (EC) dysfunction is one of the first triggers initiating this process. EC dysfunction leads to the activation of several cellular signalling pathways in the endothelium, resulting in the uncontrolled proliferation of ECs, pulmonary artery smooth muscle cells, and fibroblasts, and eventually leads to vascular remodelling and the occlusion of the pulmonary blood vessels. Other factors that are related to EC dysfunction in PAH are an increase in endothelial to mesenchymal transition, inflammation, apoptosis, and thrombus formation. In this review, we outline the latest advances on the role of EC dysfunction in PAH and other forms of pulmonary hypertension. We also elaborate on the molecular signals that orchestrate EC dysfunction in PAH. Understanding the role and mechanisms of EC dysfunction will unravel the therapeutic potential of targeting this process in PAH. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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28 pages, 2055 KiB  
Review
Endothelial Dysfunction in Diabetes Is Aggravated by Glycated Lipoproteins; Novel Molecular Therapies
by Laura Toma, Camelia Sorina Stancu and Anca Volumnia Sima
Biomedicines 2021, 9(1), 18; https://doi.org/10.3390/biomedicines9010018 - 27 Dec 2020
Cited by 25 | Viewed by 4548
Abstract
Diabetes and its vascular complications affect an increasing number of people. This disease of epidemic proportion nowadays involves abnormalities of large and small blood vessels, all commencing with alterations of the endothelial cell (EC) functions. Cardiovascular diseases are a major cause of death [...] Read more.
Diabetes and its vascular complications affect an increasing number of people. This disease of epidemic proportion nowadays involves abnormalities of large and small blood vessels, all commencing with alterations of the endothelial cell (EC) functions. Cardiovascular diseases are a major cause of death and disability among diabetic patients. In diabetes, EC dysfunction (ECD) is induced by the pathological increase of glucose and by the appearance of advanced glycation end products (AGE) attached to the plasma proteins, including lipoproteins. AGE proteins interact with their specific receptors on EC plasma membrane promoting activation of signaling pathways, resulting in decreased nitric oxide bioavailability, increased intracellular oxidative and inflammatory stress, causing dysfunction and finally apoptosis of EC. Irreversibly glycated lipoproteins (AGE-Lp) were proven to have an important role in accelerating atherosclerosis in diabetes. The aim of the present review is to present up-to-date information connecting hyperglycemia, ECD and two classes of glycated Lp, glycated low-density lipoproteins and glycated high-density lipoproteins, which contribute to the aggravation of diabetes complications. We will highlight the role of dyslipidemia, oxidative and inflammatory stress and epigenetic risk factors, along with the specific mechanisms connecting them, as well as the new promising therapies to alleviate ECD in diabetes. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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26 pages, 2479 KiB  
Review
Can Metformin Exert as an Active Drug on Endothelial Dysfunction in Diabetic Subjects?
by Teresa Salvatore, Pia Clara Pafundi, Raffaele Galiero, Luca Rinaldi, Alfredo Caturano, Erica Vetrano, Concetta Aprea, Gaetana Albanese, Anna Di Martino, Carmen Ricozzi, Simona Imbriani and Ferdinando Carlo Sasso
Biomedicines 2021, 9(1), 3; https://doi.org/10.3390/biomedicines9010003 - 22 Dec 2020
Cited by 67 | Viewed by 5857
Abstract
Cardiovascular mortality is a major cause of death among in type 2 diabetes (T2DM). Endothelial dysfunction (ED) is a well-known important risk factor for the development of diabetes cardiovascular complications. Therefore, the prevention of diabetic macroangiopathies by preserving endothelial function represents a major [...] Read more.
Cardiovascular mortality is a major cause of death among in type 2 diabetes (T2DM). Endothelial dysfunction (ED) is a well-known important risk factor for the development of diabetes cardiovascular complications. Therefore, the prevention of diabetic macroangiopathies by preserving endothelial function represents a major therapeutic concern for all National Health Systems. Several complex mechanisms support ED in diabetic patients, frequently cross-talking each other: uncoupling of eNOS with impaired endothelium-dependent vascular response, increased ROS production, mitochondrial dysfunction, activation of polyol pathway, generation of advanced glycation end-products (AGEs), activation of protein kinase C (PKC), endothelial inflammation, endothelial apoptosis and senescence, and dysregulation of microRNAs (miRNAs). Metformin is a milestone in T2DM treatment. To date, according to most recent EASD/ADA guidelines, it still represents the first-choice drug in these patients. Intriguingly, several extraglycemic effects of metformin have been recently observed, among which large preclinical and clinical evidence support metformin’s efficacy against ED in T2DM. Metformin seems effective thanks to its favorable action on all the aforementioned pathophysiological ED mechanisms. AMPK pharmacological activation plays a key role, with metformin inhibiting inflammation and improving ED. Therefore, aim of this review is to assess metformin’s beneficial effects on endothelial dysfunction in T2DM, which could preempt development of atherosclerosis. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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17 pages, 3330 KiB  
Review
Endothelial to Mesenchymal Transition in Pulmonary Vascular Diseases
by Eunsik Yun, Yunjin Kook, Kyung Hyun Yoo, Keun Il Kim, Myeong-Sok Lee, Jongmin Kim and Aram Lee
Biomedicines 2020, 8(12), 639; https://doi.org/10.3390/biomedicines8120639 - 21 Dec 2020
Cited by 19 | Viewed by 4573
Abstract
Lung diseases, such as pulmonary hypertension and pulmonary fibrosis, are life-threatening diseases and have common features of vascular remodeling. During progression, extracellular matrix protein deposition and dysregulation of proteolytic enzymes occurs, which results in vascular stiffness and dysfunction. Although vasodilators or anti-fibrotic therapy [...] Read more.
Lung diseases, such as pulmonary hypertension and pulmonary fibrosis, are life-threatening diseases and have common features of vascular remodeling. During progression, extracellular matrix protein deposition and dysregulation of proteolytic enzymes occurs, which results in vascular stiffness and dysfunction. Although vasodilators or anti-fibrotic therapy have been mainly used as therapy owing to these characteristics, their effectiveness does not meet expectations. Therefore, a better understanding of the etiology and new therapeutic approaches are needed. Endothelial cells (ECs) line the inner walls of blood vessels and maintain vascular homeostasis by protecting vascular cells from pathological stimuli. Chronic stimulation of ECs by various factors, including pro-inflammatory cytokines and hypoxia, leads to ECs undergoing an imbalance of endothelial homeostasis, which results in endothelial dysfunction and is closely associated with vascular diseases. Emerging studies suggest that endothelial to mesenchymal transition (EndMT) contributes to endothelial dysfunction and plays a key role in the pathogenesis of vascular diseases. EndMT is a process by which ECs lose their markers and show mesenchymal-like morphological changes, and gain mesenchymal cell markers. Despite the efforts to elucidate these molecular mechanisms, the role of EndMT in the pathogenesis of lung disease still requires further investigation. Here, we review the importance of EndMT in the pathogenesis of pulmonary vascular diseases and discuss various signaling pathways and mediators involved in the EndMT process. Furthermore, we will provide insight into the therapeutic potential of targeting EndMT. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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21 pages, 1348 KiB  
Review
Molecular and Cellular Mechanisms of Electronegative Lipoproteins in Cardiovascular Diseases
by Liang-Yin Ke, Shi Hui Law, Vineet Kumar Mishra, Farzana Parveen, Hua-Chen Chan, Ye-Hsu Lu and Chih-Sheng Chu
Biomedicines 2020, 8(12), 550; https://doi.org/10.3390/biomedicines8120550 - 29 Nov 2020
Cited by 17 | Viewed by 3978
Abstract
Dysregulation of glucose and lipid metabolism increases plasma levels of lipoproteins and triglycerides, resulting in vascular endothelial damage. Remarkably, the oxidation of lipid and lipoprotein particles generates electronegative lipoproteins that mediate cellular deterioration of atherosclerosis. In this review, we examined the core of [...] Read more.
Dysregulation of glucose and lipid metabolism increases plasma levels of lipoproteins and triglycerides, resulting in vascular endothelial damage. Remarkably, the oxidation of lipid and lipoprotein particles generates electronegative lipoproteins that mediate cellular deterioration of atherosclerosis. In this review, we examined the core of atherosclerotic plaque, which is enriched by byproducts of lipid metabolism and lipoproteins, such as oxidized low-density lipoproteins (oxLDL) and electronegative subfraction of LDL (LDL(−)). We also summarized the chemical properties, receptors, and molecular mechanisms of LDL(−). In combination with other well-known markers of inflammation, namely metabolic diseases, we concluded that LDL(−) can be used as a novel prognostic tool for these lipid disorders. In addition, through understanding the underlying pathophysiological molecular routes for endothelial dysfunction and inflammation, we may reassess current therapeutics and might gain a new direction to treat atherosclerotic cardiovascular diseases, mainly targeting LDL(−) clearance. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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24 pages, 1017 KiB  
Review
Arginine and Endothelial Function
by Jessica Gambardella, Wafiq Khondkar, Marco Bruno Morelli, Xujun Wang, Gaetano Santulli and Valentina Trimarco
Biomedicines 2020, 8(8), 277; https://doi.org/10.3390/biomedicines8080277 - 06 Aug 2020
Cited by 126 | Viewed by 12755
Abstract
Arginine (L-arginine), is an amino acid involved in a number of biological processes, including the biosynthesis of proteins, host immune response, urea cycle, and nitric oxide production. In this systematic review, we focus on the functional role of arginine in the regulation of [...] Read more.
Arginine (L-arginine), is an amino acid involved in a number of biological processes, including the biosynthesis of proteins, host immune response, urea cycle, and nitric oxide production. In this systematic review, we focus on the functional role of arginine in the regulation of endothelial function and vascular tone. Both clinical and preclinical studies are examined, analyzing the effects of arginine supplementation in hypertension, ischemic heart disease, aging, peripheral artery disease, and diabetes mellitus. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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15 pages, 870 KiB  
Review
Clinical Significance of Electronegative Low-Density Lipoprotein Cholesterol in Atherothrombosis
by Chih-Sheng Chu, Shi Hui Law, David Lenzen, Yong-Hong Tan, Shih-Feng Weng, Etsuro Ito, Jung-Chou Wu, Chu-Huang Chen, Hua-Chen Chan and Liang-Yin Ke
Biomedicines 2020, 8(8), 254; https://doi.org/10.3390/biomedicines8080254 - 30 Jul 2020
Cited by 11 | Viewed by 3905
Abstract
Despite the numerous risk factors for atherosclerotic cardiovascular diseases (ASCVD), cumulative evidence shows that electronegative low-density lipoprotein (L5 LDL) cholesterol is a promising biomarker. Its toxicity may contribute to atherothrombotic events. Notably, plasma L5 LDL levels positively correlate with the increasing severity of [...] Read more.
Despite the numerous risk factors for atherosclerotic cardiovascular diseases (ASCVD), cumulative evidence shows that electronegative low-density lipoprotein (L5 LDL) cholesterol is a promising biomarker. Its toxicity may contribute to atherothrombotic events. Notably, plasma L5 LDL levels positively correlate with the increasing severity of cardiovascular diseases. In contrast, traditional markers such as LDL-cholesterol and triglyceride are the therapeutic goals in secondary prevention for ASCVD, but that is controversial in primary prevention for patients with low risk. In this review, we point out the clinical significance and pathophysiological mechanisms of L5 LDL, and the clinical applications of L5 LDL levels in ASCVD can be confidently addressed. Based on the previously defined cut-off value by receiver operating characteristic curve, the acceptable physiological range of L5 concentration is proposed to be below 1.7 mg/dL. When L5 LDL level surpass this threshold, clinically relevant ASCVD might be present, and further exams such as carotid intima-media thickness, pulse wave velocity, exercise stress test, or multidetector computed tomography are required. Notably, the ultimate goal of L5 LDL concentration is lower than 1.7 mg/dL. Instead, with L5 LDL greater than 1.7 mg/dL, lipid-lowering treatment may be required, including statin, ezetimibe or PCSK9 inhibitor, regardless of the low-density lipoprotein cholesterol (LDL-C) level. Since L5 LDL could be a promising biomarker, we propose that a high throughput, clinically feasible methodology is urgently required not only for conducting a prospective, large population study but for developing therapeutics strategies to decrease L5 LDL in the blood. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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15 pages, 684 KiB  
Review
Endothelial Dysfunction in Diabetes
by Yusuke Takeda, Keiichiro Matoba, Kensuke Sekiguchi, Yosuke Nagai, Tamotsu Yokota, Kazunori Utsunomiya and Rimei Nishimura
Biomedicines 2020, 8(7), 182; https://doi.org/10.3390/biomedicines8070182 - 29 Jun 2020
Cited by 40 | Viewed by 9609
Abstract
Diabetes is a worldwide health issue closely associated with cardiovascular events. Given the pandemic of obesity, the identification of the basic underpinnings of vascular disease is strongly needed. Emerging evidence has suggested that endothelial dysfunction is a critical step in the progression of [...] Read more.
Diabetes is a worldwide health issue closely associated with cardiovascular events. Given the pandemic of obesity, the identification of the basic underpinnings of vascular disease is strongly needed. Emerging evidence has suggested that endothelial dysfunction is a critical step in the progression of atherosclerosis. However, how diabetes affects the endothelium is poorly understood. Experimental and clinical studies have illuminated the tight link between insulin resistance and endothelial dysfunction. In addition, macrophage polarization from M2 towards M1 contributes to the process of endothelial damage. The possibility that novel classes of anti-hyperglycemic agents exert beneficial effects on the endothelial function and macrophage polarization has been raised. In this review, we discuss the current status of knowledge regarding the pathological significance of insulin signaling in endothelium. Finally, we summarize recent therapeutic strategies against endothelial dysfunction with an emphasis on macrophage polarity. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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12 pages, 925 KiB  
Review
The Biological Role of Apurinic/Apyrimidinic Endonuclease1/Redox Factor-1 as a Therapeutic Target for Vascular Inflammation and as a Serologic Biomarker
by Yu Ran Lee, Hee Kyoung Joo and Byeong Hwa Jeon
Biomedicines 2020, 8(3), 57; https://doi.org/10.3390/biomedicines8030057 - 10 Mar 2020
Cited by 19 | Viewed by 3806
Abstract
Endothelial dysfunction promotes vascular inflammation by inducing the production of reactive oxygen species and adhesion molecules. Vascular inflammation plays a key role in the pathogenesis of vascular diseases and atherosclerotic disorders. However, whether there is an endogenous system that can participate in circulating [...] Read more.
Endothelial dysfunction promotes vascular inflammation by inducing the production of reactive oxygen species and adhesion molecules. Vascular inflammation plays a key role in the pathogenesis of vascular diseases and atherosclerotic disorders. However, whether there is an endogenous system that can participate in circulating immune surveillance or managing a balance in homeostasis is unclear. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (henceforth referred to as APE1/Ref-1) is a multifunctional protein that can be secreted from cells. It functions as an apurinic/apyrimidinic endonuclease in the DNA base repair pathway and modulates redox status and several types of transcriptional factors, in addition to its anti-inflammatory activity. Recently, it was reported that the secretion of APE1/Ref-1 into the extracellular medium of cultured cells or its presence in the plasma can act as a serological biomarker for certain disorders. In this review, we summarize the possible biological functions of APE1/Ref-1 according to its subcellular localization or its extracellular secretions, as therapeutic targets for vascular inflammation and as a serologic biomarker. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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12 pages, 578 KiB  
Review
Endothelial Aldehyde Dehydrogenase 2 as a Target to Maintain Vascular Wellness and Function in Ageing
by Ginevra Nannelli, Marina Ziche, Sandra Donnini and Lucia Morbidelli
Biomedicines 2020, 8(1), 4; https://doi.org/10.3390/biomedicines8010004 - 03 Jan 2020
Cited by 14 | Viewed by 3958
Abstract
Endothelial cells are the main determinants of vascular function, since their dysfunction in response to a series of cardiovascular risk factors is responsible for disease progression and further consequences. Endothelial dysfunction, if not resolved, further aggravates the oxidative status and vessel wall inflammation, [...] Read more.
Endothelial cells are the main determinants of vascular function, since their dysfunction in response to a series of cardiovascular risk factors is responsible for disease progression and further consequences. Endothelial dysfunction, if not resolved, further aggravates the oxidative status and vessel wall inflammation, thus igniting a vicious cycle. We have furthermore to consider the physiological manifestation of vascular dysfunction and chronic low-grade inflammation during ageing, also known as inflammageing. Based on these considerations, knowledge of the molecular mechanism(s) responsible for endothelial loss-of-function can be pivotal to identify novel targets of intervention with the aim of maintaining endothelial wellness and vessel trophism and function. In this review we have examined the role of the detoxifying enzyme aldehyde dehydrogenase 2 (ALDH2) in the maintenance of endothelial function. Its impairment indeed is associated with oxidative stress and ageing, and in the development of atherosclerosis and neurodegenerative diseases. Strategies to improve its expression and activity may be beneficial in these largely diffused disorders. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)
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