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Molecular Mechanisms of Endothelial Dysfunction: Fourth Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 20 July 2025 | Viewed by 8658

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Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239, USA
Interests: endothelial dysfunction; cerebrovascular disease; JAK-STAT; therapeutic ultrasound
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Special Issue Information

Dear Colleagues,

A Special Issue on the “Molecular Mechanisms of Endothelial Dysfunction” is being prepared for the journal IJMS. Endothelial cells form a monolayer lining the luminal surface of every blood vessel; however, these cells do much more than simply create a physical barrier between circulating blood and tissues. Endothelial cells are heterogeneous in nature, with characteristics depending on vessel size and organ, with highly specialized cells found in the brain and kidney. The endothelium is essential for vascular homeostasis, responding to chemical and physical stimuli in a paracrine, autocrine, and endocrine manner to maintain vasomotor and tissue homeostasis, producing a range of factors that regulate vascular tone, thrombosis, cellular adhesion, inflammation, and smooth muscle proliferation. A functional endothelium and vasculature are essential to tissue health and function.

When endothelial cells become dysfunctional, they lose their ability to maintain homeostasis and gain other properties leading to consequences for both the vessels and the organs they supply. Traditionally, endothelial dysfunction was described as an impaired ability to generate nitric oxide by the endothelium, leading to increased oxidative stress; however, additional markers are now also used depending on organ, such as barrier integrity for cerebrovascular endothelial cells. Endothelial dysfunction may occur as a consequence, as well as contribute to the pathogenesis of many diseases including atherosclerosis, hypertension, type II diabetes, small vessel disease, vascular dementia, Alzheimer’s disease, chronic kidney disease, and stroke, with emerging evidence suggesting that endothelial dysfunction also occurs in complications associated with COVID-19. Endothelial dysfunction is a complex process involving many signaling pathways, depending on organ, vessel size, and sex, among other factors.

The elucidation of molecular mechanisms involved in endothelial dysfunction is crucial for the development of efficient therapies to improve endothelial function and vascular homeostasis in disease. This Special Issue invites the submission of original research articles and reviews presenting current studies into the molecular processes in endothelial homeostasis and how perturbation of these leads to endothelial dysfunction.

Dr. Catherine Davis
Guest Editor

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Keywords

  • vascular permeability
  • atherosclerosis
  • blood–brain barrier
  • endothelial adhesion molecules
  • vasodilation
  • thrombosis

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Published Papers (5 papers)

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Research

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20 pages, 4975 KiB  
Article
BRAF Modulates the Interplay Between Cell–Cell and Cell–Extracellular Matrix Adhesions in PECAM-1-Mediated Mechanotransduction
by Éva Gráczer, Katalin Pászty, Laura Harsányi, Csilla Lehoczky, Antónia Fülöp and Andrea Varga
Int. J. Mol. Sci. 2024, 25(20), 11234; https://doi.org/10.3390/ijms252011234 - 18 Oct 2024
Cited by 1 | Viewed by 1552
Abstract
Mechanotransduction, the process of how cells sense and convert mechanical stimuli into biochemical response, is crucial in the migration of leukocytes or cancer cells through the endothelium during inflammation or metastasis. Migrating cells exert forces on the endothelium through cell surface adhesion molecules, [...] Read more.
Mechanotransduction, the process of how cells sense and convert mechanical stimuli into biochemical response, is crucial in the migration of leukocytes or cancer cells through the endothelium during inflammation or metastasis. Migrating cells exert forces on the endothelium through cell surface adhesion molecules, such as platelet endothelial adhesion molecule PECAM-1, and this is essential for a successful transmigration. To study PECAM-1-mediated mechanotransduction, we applied PECAM-1-antibody-coated magnetic beads and exerted about 40 pN force on the endothelial monolayer. We show that force increases cell–ECM adhesion in the cell center and is accompanied by the opening of cell–cell junctions. Upon depletion of the MEK/ERK kinase, BRAF force increases cell–ECM adhesion both at the cell periphery and in the cell center, but this does not result in the opening of cell–cell junctions. Decreasing cell–ECM adhesion in BRAF-depleted cells through FAK inhibition results in the remodeling of cell–cell junctions. Force-induced increase in cell–ECM adhesion in the cell center correlates with the activation of the transcriptional cofactor Yes-associated protein (YAP). Furthermore, the induced activation of YAP through LATS inhibition prevents junctional remodeling in control cells. Thus, the activation of YAP might determine the strength of cell–cell junctions during PECAM-1-mediated mechanotransduction. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction: Fourth Edition)
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17 pages, 4106 KiB  
Article
Replicative Endothelial Cell Senescence May Lead to Endothelial Dysfunction by Increasing the BH2/BH4 Ratio Induced by Oxidative Stress, Reducing BH4 Availability, and Decreasing the Expression of eNOS
by Ignacio Hernandez-Navarro, Laura Botana, Javier Diez-Mata, Laura Tesoro, Beatriz Jimenez-Guirado, Claudia Gonzalez-Cucharero, Nunzio Alcharani, Jose Luis Zamorano, Marta Saura and Carlos Zaragoza
Int. J. Mol. Sci. 2024, 25(18), 9890; https://doi.org/10.3390/ijms25189890 - 13 Sep 2024
Cited by 2 | Viewed by 2161
Abstract
Vascular aging is associated with the development of cardiovascular complications, in which endothelial cell senescence (ES) may play a critical role. Nitric oxide (NO) prevents human ES through inhibition of oxidative stress, and inflammatory signaling by mechanisms yet to be elucidated. Endothelial cells [...] Read more.
Vascular aging is associated with the development of cardiovascular complications, in which endothelial cell senescence (ES) may play a critical role. Nitric oxide (NO) prevents human ES through inhibition of oxidative stress, and inflammatory signaling by mechanisms yet to be elucidated. Endothelial cells undergo an irreversible growth arrest and alter their functional state after a finite number of divisions, a phenomenon called replicative senescence. We assessed the contribution of NO during replicative senescence of human aortic (HAEC) and coronary (CAEC) endothelial cells, in which accumulation of the senescence marker SA-β-Gal was quantified by β-galactosidase staining on cultured cells. We found a negative correlation in passaged cell cultures from P0 to P12, between a reduction in NO production with increased ES and the formation of reactive oxygen (ROS) and nitrogen (ONOO) species, indicative of oxidative and nitrosative stress. The effect of ES was evidenced by reduced expression of endothelial Nitric Oxide Synthase (eNOS), Interleukin Linked Kinase (ILK), and Heat shock protein 90 (Hsp90), alongside a significant increase in the BH2/BH4 ratio, inducing the uncoupling of eNOS, favoring the production of superoxide and peroxynitrite species, and fostering an inflammatory environment, as confirmed by the levels of Cyclophilin A (CypA) and its receptor Extracellular Matrix Metalloprotease Inducer (EMMPRIN). NO prevents ES by preventing the uncoupling of eNOS, in which oxidation of BH4, which plays a key role in eNOS producing NO, may play a critical role in launching the release of free radical species, triggering an aging-related inflammatory response. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction: Fourth Edition)
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Review

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27 pages, 859 KiB  
Review
Molecular Mechanisms of Vascular Tone in Exercising Pediatric Populations: A Comprehensive Overview on Endothelial, Antioxidative, Metabolic and Lipoprotein Signaling Molecules
by Jonas Haferanke, Lisa Baumgartner, Laura Willinger, Renate Oberhoffer-Fritz and Thorsten Schulz
Int. J. Mol. Sci. 2025, 26(3), 1027; https://doi.org/10.3390/ijms26031027 - 25 Jan 2025
Viewed by 900
Abstract
Vasoactive molecules are central regulators of vascular tone, angiogenesis and inflammation. Key molecular agents include nitric oxide (NO), endothelin-1 (ET-1), prostacyclin, free triiodothyronine (fT3), leptin, low-density lipoprotein (LDL), high-density lipoprotein (HDL), superoxide dismutase (SOD), and glutathione peroxidase (GPX). Dysregulation of these compounds can [...] Read more.
Vasoactive molecules are central regulators of vascular tone, angiogenesis and inflammation. Key molecular agents include nitric oxide (NO), endothelin-1 (ET-1), prostacyclin, free triiodothyronine (fT3), leptin, low-density lipoprotein (LDL), high-density lipoprotein (HDL), superoxide dismutase (SOD), and glutathione peroxidase (GPX). Dysregulation of these compounds can lead to endothelial dysfunction, an early predictor of atherosclerosis and cardiovascular diseases (CVD). Maintaining endothelial health is thus essential for vascular homeostasis and cardiovascular risk prevention. Regular exercise serves as a vital protective measure against CVD and the risk of cardiovascular conditions. However, young athletes often significantly exceed recommended levels of training load, engaging in highly intensive training that leads to substantial physiological adaptations. Despite this, research on the impact of exercise on vasoactive substances in children and adolescents, particularly young athletes, is limited and inconsistent. Most studies focus on those with pre-existing conditions, like obesity or diabetes mellitus. Existing findings suggest exercise may favorably affect vascular biomarkers in youth, but methodological variations hinder consistent conclusions. This literature review examines 68 studies on the effects of exercise on vascular molecules in children and adolescents, young athletes, and children and adolescents with pre-existing conditions, offering deeper insights into how exercise may influence vascular health at the molecular level. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction: Fourth Edition)
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19 pages, 1442 KiB  
Review
Extracellular Vesicles as Mediators of Endothelial Dysfunction in Cardiovascular Diseases
by Francisco Rafael Jimenez-Trinidad, Sergi Calvo-Gomez, Manel Sabaté, Salvatore Brugaletta, Victoria Campuzano, Gustavo Egea and Ana Paula Dantas
Int. J. Mol. Sci. 2025, 26(3), 1008; https://doi.org/10.3390/ijms26031008 - 24 Jan 2025
Cited by 2 | Viewed by 1904
Abstract
This comprehensive review aims to provide a thorough overview of the vital role that extracellular vesicles (EVs) play in endothelial dysfunction, particularly emphasizing how physiological factors—such as sex and aging—along with significant cardiovascular risk factors, influence this process. The review covers studies ranging [...] Read more.
This comprehensive review aims to provide a thorough overview of the vital role that extracellular vesicles (EVs) play in endothelial dysfunction, particularly emphasizing how physiological factors—such as sex and aging—along with significant cardiovascular risk factors, influence this process. The review covers studies ranging from the first description of EVs in 1945 to contemporary insights into their biological roles in intercellular signaling and endothelial dysfunction. A comprehensive analysis of peer-reviewed articles and reviews indexed in the PubMed database was conducted to compile the information. Initially, Medical Subject Headings (MeSH) terms included keywords aimed at providing general knowledge about the role of EVs in the regulation of endothelial signaling, such as “extracellular vesicles”, “endothelium”, and “intercellular signaling”. Subsequently, terms related to the pathophysiological implications of EV interactions with endothelial dysfunction and cardiovascular disease were added, including “cardiovascular disease”, “sex”, “aging”, “atherosclerosis”, “obesity”, and “diabetes”. Additionally, the potential applications of EVs in cardiovascular disease were explored using the MeSH terms “extracellular vesicles”, “cardiovascular disease”, “biomarker”, and “therapeutic strategy”. The results of this bibliographical review reveal that EVs have the capacity to induce various cellular responses within the cardiovascular system and play a significant role in the complex landscape of endothelial dysfunction and cardiovascular disease. The composition of the EV cargo is subject to modification by pathophysiological conditions such as sex, aging, and cardiovascular risk factors, which result in a complex regulatory influence on endothelial function and neighboring cells when released from a dysfunctional endothelium. Moreover, the data suggest that this field still requires further exploration, as EV biology is continuously evolving, presenting a dynamic and engaging area for research. A deeper understanding of the molecular cargo involved in EV–endothelium interactions could yield valuable biomarkers for monitoring cardiovascular disease progression and facilitate the development of innovative bioengineered therapeutic strategies to enhance patient outcomes. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction: Fourth Edition)
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23 pages, 2766 KiB  
Review
Immune and Metabolic Mechanisms of Endothelial Dysfunction
by Irakli Kopaliani, Basant Elsaid, Stephan Speier and Andreas Deussen
Int. J. Mol. Sci. 2024, 25(24), 13337; https://doi.org/10.3390/ijms252413337 - 12 Dec 2024
Cited by 2 | Viewed by 1438
Abstract
Endothelial dysfunction is a strong prognostic factor in predicting the development of cardiovascular diseases. Dysfunctional endothelium loses its homeostatic ability to regulate vascular tone and prevent overactivation of inflammation, leading to vascular dysfunction. These functions are critical for vascular homeostasis and arterial pressure [...] Read more.
Endothelial dysfunction is a strong prognostic factor in predicting the development of cardiovascular diseases. Dysfunctional endothelium loses its homeostatic ability to regulate vascular tone and prevent overactivation of inflammation, leading to vascular dysfunction. These functions are critical for vascular homeostasis and arterial pressure control, the disruption of which may lead to hypertension. Hypertension itself can also cause endothelial dysfunction, as endothelial cells are susceptible to haemodynamic changes. Although it is unclear which of those factors appear first, they create a vicious circle further damaging multiple organs, including the heart and vessels. There are also sex-specific differences in homeostatic functions of the endothelium regarding vessel tone regulation, which may contribute to differences in arterial blood pressure between men and women. Even more importantly, there are sex-differences in the development of endothelial dysfunction and vessel remodelling. Hence, an understanding of the mechanisms of endothelial dysfunction and its contribution to pathological vascular remodelling during hypertension is of critical importance. This review addresses immunological and metabolic aspects in mechanisms of endothelial dysfunction and the resulting mechanisms in vascular remodelling with respect to arterial hypertension, including the potential role of sex-specific differences. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction: Fourth Edition)
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