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Molecular Mechanisms of Endothelial Dysfunction

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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: closed (30 June 2022) | Viewed by 30180

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Dr. Catherine Davis

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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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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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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

vascular permeability
atherosclerosis
blood brain barrier
endothelial adhesion molecules
vasodilation
thrombosis

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Molecular Mechanisms of Endothelial Dysfunction: Fourth Edition in International Journal of Molecular Sciences (2 articles)

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Research

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15 pages, 3085 KiB

Open AccessArticle

Role of Endothelial STAT3 in Cerebrovascular Function and Protection from Ischemic Brain Injury

by Catherine M. Davis, Kristin Lyon-Scott, Elena V. Varlamov, Wenri H. Zhang and Nabil J. Alkayed

Int. J. Mol. Sci. 2022, 23(20), 12167; https://doi.org/10.3390/ijms232012167 - 12 Oct 2022

Cited by 5 | Viewed by 2036

Abstract

STAT3 plays a protective role against ischemic brain injury; however, it is not clear which brain cell type mediates this effect, and by which mechanism. We tested the hypothesis that endothelial STAT3 contributes to protection from cerebral ischemia, by preserving cerebrovascular endothelial function and blood–brain barrier (BBB) integrity. The objective of this study was to determine the role of STAT3 in cerebrovascular endothelial cell (EC) survival and function, and its role in tissue outcome after cerebral ischemia. We found that in primary mouse brain microvascular ECs, STAT3 was constitutively active, and its phosphorylation was reduced by oxygen-glucose deprivation (OGD), recovering after re-oxygenation. STAT3 inhibition, using two mechanistically different pharmacological inhibitors, increased EC injury after OGD. The sub-lethal inhibition of STAT3 caused endothelial dysfunction, demonstrated by reduced nitric oxide release in response to acetylcholine and reduced barrier function of the endothelial monolayer. Finally, mice with reduced endothelial STAT3 (Tie2-Cre; STAT3^flox/wt) sustained larger brain infarcts after middle cerebral artery occlusion (MCAO) compared to wild-type (WT) littermates. We conclude that STAT3 is vital to maintaining cerebrovascular integrity, playing a role in EC survival and function, and protection against cerebral ischemia. Endothelial STAT3 may serve as a potential target in preventing endothelial dysfunction after stroke. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction)

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12 pages, 1466 KiB

Open AccessArticle

Assessment of the Proton Pump Inhibitor, Esomeprazole Magnesium Hydrate and Trihydrate, on Pathophysiological Markers of Preeclampsia in Preclinical Human Models of Disease

by Natasha de Alwis, Bianca R. Fato, Sally Beard, Natalie K. Binder, Tu’uhevaha J. Kaitu’u-Lino, Kenji Onda and Natalie J. Hannan

Int. J. Mol. Sci. 2022, 23(17), 9533; https://doi.org/10.3390/ijms23179533 - 23 Aug 2022

Cited by 5 | Viewed by 2388

Abstract

Previously, we demonstrated that the proton pump inhibitor, esomeprazole magnesium hydrate (MH), could have potential as a repurposed treatment against preeclampsia, a serious obstetric condition. In this study we investigate the difference in the preclinical effectiveness between 100 µM of esomeprazole MH and its hydration isomer, esomeprazole magnesium trihydrate (MTH). Here, we found that both treatments reduced secretion of sFLT-1 (anti-angiogenic factor) from primary cytotrophoblast, but only esomeprazole MH reduced sFLT-1 secretion from primary human umbilical vein endothelial cells (assessed via ELISA). Both drugs could mitigate expression of the endothelial dysfunction markers, vascular cell adhesion molecule-1 and endothelin-1 (via qPCR). Neither esomeprazole MH nor MTH quenched cytotrophoblast reactive oxygen species production in response to sodium azide (ROS assay). Finally, using wire myography, we demonstrated that both compounds were able to induce vasodilation of human omental arteries at 100 µM. Esomeprazole is safe to use in pregnancy and a candidate treatment for preeclampsia. Using primary human tissues and cells, we validated that esomeprazole is effective in enhancing vascular relaxation, and can reduce key factors associated with preeclampsia, including sFLT-1 and endothelial dysfunction. However, esomeprazole MH was more efficacious than esomeprazole MTH in our in vitro studies. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction)

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16 pages, 5125 KiB

Open AccessArticle

Actions of Esomeprazole on the Maternal Vasculature in Lean and Obese Pregnant Mice with Impaired Nitric Oxide Synthesis: A Model of Preeclampsia

by Natasha de Alwis, Natalie K. Binder, Yeukai T. M. Mangwiro, Sally Beard, Natasha Pritchard, Elif Kadife, Bianca R. Fato, Emerson Keenan, Fiona C. Brownfoot, Tu’uhevaha J. Kaitu’u-Lino and Natalie J. Hannan

Int. J. Mol. Sci. 2022, 23(15), 8185; https://doi.org/10.3390/ijms23158185 - 25 Jul 2022

Cited by 2 | Viewed by 2515

Abstract

Preeclampsia is a devastating, multisystem disorder of pregnancy. It has no cure except delivery, which if premature can impart significant neonatal morbidity. Efforts to repurpose pregnancy-safe therapeutics for the treatment of preeclampsia have led to the assessment of the proton pump inhibitor, esomeprazole. Preclinically, esomeprazole reduced placental secretion of anti-angiogenic sFlt-1, improved endothelial dysfunction, promoted vasorelaxation, and reduced maternal hypertension in a mouse model. Our understanding of the precise mechanisms through which esomeprazole works to reduce endothelial dysfunction and enhance vasoreactivity is limited. Evidence from earlier studies suggested esomeprazole might work via the nitric oxide pathway, upregulating endothelial nitric oxide synthase (eNOS). Here, we investigated the effect of esomeprazole in a mouse model of L-NAME-induced hypertension (decreased eNOS activity). We further antagonised the model by addition of diet-induced obesity, which is relevant to both preeclampsia and the nitric oxide pathway. Esomeprazole did not decrease blood pressure in this model, nor were there any alterations in vasoreactivity or changes in foetal outcomes in lean mice. We observed similar findings in the obese mouse cohort, except esomeprazole treatment enhanced ex vivo acetylcholine-induced vasorelaxation. As acetylcholine induces nitric oxide production, these findings hint at a function for esomeprazole in the nitric oxide pathway. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction)

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19 pages, 4393 KiB

Open AccessArticle

Proteome-Wide Differential Effects of Peritoneal Dialysis Fluid Properties in an In Vitro Human Endothelial Cell Model

by Juan Manuel Sacnun, Robin Hoogenboom, Fabian Eibensteiner, Isabel J. Sobieszek, Markus Unterwurzacher, Anja Wagner, Rebecca Herzog and Klaus Kratochwill

Int. J. Mol. Sci. 2022, 23(14), 8010; https://doi.org/10.3390/ijms23148010 - 20 Jul 2022

Cited by 6 | Viewed by 2494

Abstract

To replace kidney function, peritoneal dialysis (PD) utilizes hyperosmotic PD fluids with specific physico-chemical properties. Their composition induces progressive damage of the peritoneum, leading to vasculopathies, decline of membrane function, and PD technique failure. Clinically used PD fluids differ in their composition but still remain bioincompatible. We mapped the molecular pathomechanisms in human endothelial cells induced by the different characteristics of widely used PD fluids by proteomics. Of 7894 identified proteins, 3871 were regulated at least by 1 and 49 by all tested PD fluids. The latter subset was enriched for cell junction-associated proteins. The different PD fluids individually perturbed proteins commonly related to cell stress, survival, and immune function pathways. Modeling two major bioincompatibility factors of PD fluids, acidosis, and glucose degradation products (GDPs) revealed distinct effects on endothelial cell function and regulation of cellular stress responses. Proteins and pathways most strongly affected were members of the oxidative stress response. Addition of the antioxidant and cytoprotective additive, alanyl-glutamine (AlaGln), to PD fluids led to upregulation of thioredoxin reductase-1, an antioxidant protein, potentially explaining the cytoprotective effect of AlaGln. In conclusion, we mapped out the molecular response of endothelial cells to PD fluids, and provided new evidence for their specific pathomechanisms, crucial for improvement of PD therapies. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction)

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26 pages, 961 KiB

Open AccessArticle

Exploratory Investigation of the Plasma Proteome Associated with the Endotheliopathy of Trauma

by Joseph D. Krocker, Kyung Hyun Lee, Hanne H. Henriksen, Yao-Wei Willa Wang, Erwin M. Schoof, Sigurdur T. Karvelsson, Óttar Rolfsson, Pär I. Johansson, Claudia Pedroza and Charles E. Wade

Int. J. Mol. Sci. 2022, 23(11), 6213; https://doi.org/10.3390/ijms23116213 - 1 Jun 2022

Cited by 7 | Viewed by 3255

Abstract

Background: The endotheliopathy of trauma (EoT) is associated with increased mortality following injury. Herein, we describe the plasma proteome related to EoT in order to provide insight into the role of the endothelium within the systemic response to trauma. Methods: 99 subjects requiring the highest level of trauma activation were included in the study. Enzyme-linked immunosorbent assays of endothelial and catecholamine biomarkers were performed on admission plasma samples, as well as untargeted proteome quantification utilizing high-performance liquid chromatography and tandem mass spectrometry. Results: Plasma endothelial and catecholamine biomarker abundance was elevated in EoT. Patients with EoT (n = 62) had an increased incidence of death within 24 h at 21% compared to 3% for non-EoT (n = 37). Proteomic analysis revealed that 52 out of 290 proteins were differentially expressed between the EoT and non-EoT groups. These proteins are involved in endothelial activation, coagulation, inflammation, and oxidative stress, and include known damage-associated molecular patterns (DAMPs) and intracellular proteins specific to several organs. Conclusions: We report a proteomic profile of EoT suggestive of a surge of DAMPs and inflammation driving nonspecific activation of the endothelial, coagulation, and complement systems with subsequent end-organ damage and poor clinical outcome. These findings support the utility of EoT as an index of cellular injury and delineate protein candidates for therapeutic intervention. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction)

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14 pages, 1999 KiB

Open AccessArticle

Hemin-Induced Endothelial Dysfunction and Endothelial to Mesenchymal Transition in the Pathogenesis of Pulmonary Hypertension Due to Chronic Hemolysis

by Janae Gonzales, Kelsey Holbert, Kamryn Czysz, Joseph George, Caroline Fernandes and Dustin R. Fraidenburg

Int. J. Mol. Sci. 2022, 23(9), 4763; https://doi.org/10.3390/ijms23094763 - 26 Apr 2022

Cited by 12 | Viewed by 2441

Abstract

Pulmonary hypertension in sickle cell disease is an independent predictor of mortality, yet the pathogenesis of pulmonary vascular disease in chronic hemolytic disorders remains incompletely understood and treatment options are limited primarily to supportive care. The release of extracellular hemoglobin has been implicated in the development of pulmonary hypertension, and in this study we explored the direct effects of hemin, the oxidized moiety of heme, on the pulmonary artery endothelium. We found that low dose hemin exposure leads to significantly increased endothelial cell proliferation, migration, and cytokine release as markers of endothelial dysfunction. Protein expression changes in our pulmonary artery endothelial cells showed upregulation of mesenchymal markers after hemin treatment in conjunction with a decrease in endothelial markers. Endothelial to mesenchymal transition (EndoMT) resulting from hemin exposure was further confirmed by showing upregulation of the transcription factors SNAI1 and SLUG, known to regulate EndoMT. Lastly, given the endothelial dysfunction and phenotypic transition observed, the endothelial cytoskeleton was considered a potential novel target. Inhibiting myosin light chain kinase, to prevent phosphorylation of myosin light chain and cytoskeletal contraction, attenuated hemin-induced endothelial hyper-proliferation, migration, and cytokine release. The findings in this study implicate hemin as a key inducer of endothelial dysfunction through EndoMT, which may play an important role in pulmonary vascular remodeling during the development of pulmonary hypertension in chronic hemolytic states. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction)

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12 pages, 1988 KiB

Open AccessArticle

Trimethylamine N-Oxide (TMAO) Impairs Purinergic Induced Intracellular Calcium Increase and Nitric Oxide Release in Endothelial Cells

by Giulia Querio, Susanna Antoniotti, Federica Geddo, Renzo Levi and Maria Pia Gallo

Int. J. Mol. Sci. 2022, 23(7), 3982; https://doi.org/10.3390/ijms23073982 - 2 Apr 2022

Cited by 20 | Viewed by 3446

Abstract

Trimethylamine N-oxide (TMAO) is a diet derived compound directly introduced through foodstuff, or endogenously synthesized from its precursors, primarily choline, L-carnitine, and ergothioneine. New evidence outlines high TMAO plasma concentrations in patients with overt cardiovascular disease, but its direct role in pathological development is still controversial. The purpose of the study was to evaluate the role of TMAO in affecting key intracellular factors involved in endothelial dysfunction development, such as reactive oxygen species, mitochondrial health, calcium balance, and nitric oxide release using bovine aortic endothelial cells (BAE-1). Cell viability and oxidative stress indicators were monitored after acute and prolonged TMAO treatment. The role of TMAO in interfering with the physiological purinergic vasodilatory mechanism after ATP stimulation was defined through measurements of the rise of intracellular calcium, nitric oxide release, and eNOS phosphorylation at Ser1179 (eNOS^Ser1179). TMAO was not cytotoxic for BAE-1 and it did not induce the rise of reactive oxygen species and impairment of mitochondrial membrane potential, either in the basal condition or in the presence of a stressor. In contrast, TMAO modified the purinergic response affecting intracellular ATP-induced calcium increase, nitric oxide release, and eNOS^Ser1179. Results obtained suggest a possible implication of TMAO in impairing the endothelial-dependent vasodilatory mechanism. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction)

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18 pages, 4189 KiB

Open AccessArticle

Metabolic Response in Endothelial Cells to Catecholamine Stimulation Associated with Increased Vascular Permeability

by Adrián López García de Lomana, Arnar Ingi Vilhjálmsson, Sarah McGarrity, Rósa Sigurðardóttir, Ósk Anuforo, Alexía Rós Viktorsdóttir, Aris Kotronoulas, Andreas Bergmann, Leifur Franzson, Haraldur Halldórsson, Hanne H. Henriksen, Charles E. Wade, Pär Ingemar Johansson and Óttar Rolfsson

Int. J. Mol. Sci. 2022, 23(6), 3162; https://doi.org/10.3390/ijms23063162 - 15 Mar 2022

Cited by 10 | Viewed by 2923

Abstract

Disruption to endothelial cell homeostasis results in an extensive variety of human pathologies that are particularly relevant to major trauma. Circulating catecholamines, such as adrenaline and noradrenaline, activate endothelial adrenergic receptors triggering a potent response in endothelial function. The regulation of the endothelial cell metabolism is distinct and profoundly important to endothelium homeostasis. However, a precise catalogue of the metabolic alterations caused by sustained high catecholamine levels that results in endothelial dysfunction is still underexplored. Here, we uncover a set of up to 46 metabolites that exhibit a dose–response relationship to adrenaline-noradrenaline equimolar treatment. The identified metabolites align with the glutathione-ascorbate cycle and the nitric oxide biosynthesis pathway. Certain key metabolites, such as arginine and reduced glutathione, displayed a differential response to treatment in early (4 h) compared to late (24 h) stages of sustained stimulation, indicative of homeostatic metabolic feedback loops. Furthermore, we quantified an increase in the glucose consumption and aerobic respiration in endothelial cells upon catecholamine stimulation. Our results indicate that oxidative stress and nitric oxide metabolic pathways are downstream consequences of endothelial cell stimulation with sustained high levels of catecholamines. A precise understanding of the metabolic response in endothelial cells to pathological levels of catecholamines will facilitate the identification of more efficient clinical interventions in trauma patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction)

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Review

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21 pages, 1524 KiB

Open AccessReview

Tissue Engineering Approaches to Uncover Therapeutic Targets for Endothelial Dysfunction in Pathological Microenvironments

by Dimitris Ntekoumes and Sharon Gerecht

Int. J. Mol. Sci. 2022, 23(13), 7416; https://doi.org/10.3390/ijms23137416 - 3 Jul 2022

Cited by 3 | Viewed by 3708

Abstract

Endothelial cell dysfunction plays a central role in many pathologies, rendering it crucial to understand the underlying mechanism for potential therapeutics. Tissue engineering offers opportunities for in vitro studies of endothelial dysfunction in pathological mimicry environments. Here, we begin by analyzing hydrogel biomaterials as a platform for understanding the roles of the extracellular matrix and hypoxia in vascular formation. We next examine how three-dimensional bioprinting has been applied to recapitulate healthy and diseased tissue constructs in a highly controllable and patient-specific manner. Similarly, studies have utilized organs-on-a-chip technology to understand endothelial dysfunction’s contribution to pathologies in tissue-specific cellular components under well-controlled physicochemical cues. Finally, we consider studies using the in vitro construction of multicellular blood vessels, termed tissue-engineered blood vessels, and the spontaneous assembly of microvascular networks in organoids to delineate pathological endothelial dysfunction. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction)

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21 pages, 974 KiB

Open AccessReview

Cortactin in Lung Cell Function and Disease

by Mounica Bandela, Patrick Belvitch, Joe G. N. Garcia and Steven M. Dudek

Int. J. Mol. Sci. 2022, 23(9), 4606; https://doi.org/10.3390/ijms23094606 - 21 Apr 2022

Cited by 12 | Viewed by 3287

Abstract

Cortactin (CTTN) is an actin-binding and cytoskeletal protein that is found in abundance in the cell cortex and other peripheral structures of most cell types. It was initially described as a target for Src-mediated phosphorylation at several tyrosine sites within CTTN, and post-translational modifications at these tyrosine sites are a primary regulator of its function. CTTN participates in multiple cellular functions that require cytoskeletal rearrangement, including lamellipodia formation, cell migration, invasion, and various other processes dependent upon the cell type involved. The role of CTTN in vascular endothelial cells is particularly important for promoting barrier integrity and inhibiting vascular permeability and tissue edema. To mediate its functional effects, CTTN undergoes multiple post-translational modifications and interacts with numerous other proteins to alter cytoskeletal structures and signaling mechanisms. In the present review, we briefly describe CTTN structure, post-translational modifications, and protein binding partners and then focus on its role in regulating cellular processes and well-established functional mechanisms, primarily in vascular endothelial cells and disease models. We then provide insights into how CTTN function affects the pathophysiology of multiple lung disorders, including acute lung injury syndromes, COPD, and asthma. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction)

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