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Special Issue "Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2019).

Special Issue Editors

Prof. Dr. Francesco Perticone
E-Mail
Guest Editor
Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro 88100, Italy
Tel. +39.0961.3647149
Interests: endothelial dysfunction; arterial stiffness; hypertension; atherosclerosis; metabolic syndrome; diabetes mellitus; cardiovascular risk; insulin resistance
Prof. Dr. Salvatore Corrao
E-Mail
Guest Editor
National Relevance and High Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy

Special Issue Information

Dear Colleagues,

Endothelial dysfunction is an early step of the atherosclerotic process. It is well established that the initiation and progression of disease, and its later activation to increase the risk of morbid events, depends on profound dynamic changes in vascular biology. The endothelium is emerged as the key regulator of vascular homeostasis, in that it has not merely a barrier function but also acts as an active signal transducer for circulating influences that modify the vessel wall phenotype. Alteration in endothelial function precedes the development of morphological atherosclerotic changes and can also contribute to lesion development and later clinical complications. Furthermore, in the last few decades, the relationship between vascular and metabolic diseases has been deeply investigated, demonstrating a close link between endothelial dysfunction and insulin resistance.

This Special Issue “Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms” will cover a selection of recent research topics and current review articles in the field of endothelial activation in cardio-metabolic diseases.

Prof. Dr. Francesco Perticone
Prof. Dr. Salvatore Corrao
Guest Editors

Manuscript Submission Information

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Keywords

  • endothelial dysfunction
  • nitric oxide
  • atherosclerosis
  • arterial stiffness
  • vascular aging
  • cardiovascular risk
  • insulin resistance

Published Papers (20 papers)

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Research

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Open AccessArticle
High Concentration of C5a-Induced Mitochondria-Dependent Apoptosis in Murine Kidney Endothelial Cells
Int. J. Mol. Sci. 2019, 20(18), 4465; https://doi.org/10.3390/ijms20184465 - 10 Sep 2019
Abstract
Patients with a relapse of idiopathic nephrotic syndrome have significantly increased levels of serum complement component 5a (C5a), and proteinuria has been noted in mice treated with C5a via changes in permeability of kidney endothelial cells (KECs) in established animal models. However, the [...] Read more.
Patients with a relapse of idiopathic nephrotic syndrome have significantly increased levels of serum complement component 5a (C5a), and proteinuria has been noted in mice treated with C5a via changes in permeability of kidney endothelial cells (KECs) in established animal models. However, the apoptosis of KECs treated with high concentrations of C5a has also been observed. As mitochondrial damage is known to be important in cell apoptosis, the aim of this study was to examine the association between C5a-induced mouse KEC apoptosis and mitochondrial damage. Mouse KECs were isolated and treated with different concentrations of C5a. Cell viability assays showed that a high-concentration mouse recombinant protein C5a (rmC5a) treatment reduced mouse KEC growth. Cell cycle phase analysis, including apoptosis (sub-G1 phase) showed an increased percentage of the subG1 phase with a high-concentration rmC5a treatment. Cytochrome c and caspase 3/9 activities were significantly induced in the mouse KECs after a high-dose rmC5a (50 ng/mL) treatment, and this was rescued by pretreatment with the C5a receptor (C5aR) inhibitor (W-54011) and N-acetylcysteine (NAC). Reactive oxygen species (ROS) formation was detected in C5a-treated mouse KECs; however, W-54011 or NAC pretreatment inhibited high-dose rmC5a-induced ROS formation and also reduced cytochrome c release, apoptotic cell formation, and apoptotic DNA fragmentation. These factors determined the apoptosis of mouse KECs treated with high-dose C5a through C5aR and subsequently led to apoptosis via ROS regeneration and cytochrome c release. The results showed that high concentrations of C5a induced mouse KEC apoptosis via a C5aR/ROS/mitochondria-dependent pathway. These findings may shed light on the potential mechanism of glomerular sclerosis, a process in idiopathic nephrotic syndrome causing renal function impairment. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessArticle
Telmisartan Lowers Elevated Blood Pressure in Psoriatic Mice without Attenuating Vascular Dysfunction and Inflammation
Int. J. Mol. Sci. 2019, 20(17), 4261; https://doi.org/10.3390/ijms20174261 - 30 Aug 2019
Abstract
Background: Psoriasis is hallmarked by vascular dysfunction, arterial hypertension, and an increased risk for cardiovascular diseases. We have shown recently that skin-driven interleukin (IL)-17A expression promotes psoriasis-like disease in mice, and this is associated with vascular inflammation, vascular dysfunction, and hypertension. As an [...] Read more.
Background: Psoriasis is hallmarked by vascular dysfunction, arterial hypertension, and an increased risk for cardiovascular diseases. We have shown recently that skin-driven interleukin (IL)-17A expression promotes psoriasis-like disease in mice, and this is associated with vascular inflammation, vascular dysfunction, and hypertension. As an intensive risk-factor reduction is recommended for psoriasis patients, we aimed to elucidate the impact of the angiotensin II receptor type 1 (AT1) antagonist telmisartan in a mouse model of severe psoriasis-like skin disease. Methods and Results: Elevated blood pressure measured by tail-cuff plethysmography in mice with keratinocyte-specific IL-17A overexpression (K14-IL-17Aind/+ mice) was significantly reduced in response to telmisartan. Importantly, vascular dysfunction, as assessed by isometric tension studies of isolated aortic rings, vascular inflammation measured by flow cytometry analysis of CD45+CD11b+ immune cells, as well as the increased peripheral oxidative stress levels assessed by L-012-enhanced chemiluminescence were not attenuated by telmisartan treatment of K14-IL-17Aind/+ mice, nor was the persisting skin inflammation. Conclusion: We provide first evidence for an effective antihypertensive treatment in experimental psoriasis by AT1 blockade, but without any impact on vascular inflammation and dysfunction in our mouse model of severe psoriasis-like skin disease. This suggests that vascular function and inflammation in psoriasis might not be attenuated as long as skin inflammation persists. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessArticle
High Mobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction
Int. J. Mol. Sci. 2019, 20(14), 3570; https://doi.org/10.3390/ijms20143570 - 22 Jul 2019
Abstract
The intestinal microbe-derived metabolite trimethylamine N-oxide (TMAO) is implicated in the pathogenesis of cardiovascular diseases (CVDs). The molecular mechanisms of how TMAO induces atherosclerosis and CVDs’ progression are still unclear. In this regard, high-mobility group box protein 1 (HMGB1), an inflammatory mediator, has [...] Read more.
The intestinal microbe-derived metabolite trimethylamine N-oxide (TMAO) is implicated in the pathogenesis of cardiovascular diseases (CVDs). The molecular mechanisms of how TMAO induces atherosclerosis and CVDs’ progression are still unclear. In this regard, high-mobility group box protein 1 (HMGB1), an inflammatory mediator, has been reported to disrupt cell–cell junctions, resulting in vascular endothelial hyper permeability leading to endothelial dysfunction. The present study tested whether TMAO associated endothelial dysfunction results via HMGB1 activation. Biochemical and RT-PCR analysis showed that TMAO increased the HMGB1 expression in a dose-dependent manner in endothelial cells. However, prior treatment with glycyrrhizin, an HMGB1 binder, abolished the TMAO-induced HMGB1 production in endothelial cells. Furthermore, Western blot and immunofluorescent analysis showed significant decrease in the expression of cell–cell junction proteins ZO-2, Occludin, and VE-cadherin in TMAO treated endothelial cells compared with control cells. However, prior treatment with glycyrrhizin attenuated the TMAO-induced cell–cell junction proteins’ disruption. TMAO increased toll-like receptor 4 (TLR4) expression in endothelial cells. Inhibition of TLR4 expression by TLR4 siRNA protected the endothelial cells from TMAO associated tight junction protein disruption via HMGB1. In conclusion, our results demonstrate that HMGB1 is one of the important mediators of TMAO-induced endothelial dysfunction. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessArticle
Premature Vascular Aging in Guinea Pigs Affected by Fetal Growth Restriction
Int. J. Mol. Sci. 2019, 20(14), 3474; https://doi.org/10.3390/ijms20143474 - 15 Jul 2019
Abstract
Cardiovascular risk associated with fetal growth restriction (FGR) could result from an early impaired vascular function. However, whether this effect results in premature vascular aging has not been addressed. We studied the ex vivo reactivity of carotid and femoral arteries in fetal (near [...] Read more.
Cardiovascular risk associated with fetal growth restriction (FGR) could result from an early impaired vascular function. However, whether this effect results in premature vascular aging has not been addressed. We studied the ex vivo reactivity of carotid and femoral arteries in fetal (near term), adults (eight months-old) and aged (16 months-old) guinea pigs in normal (control) and FGR offspring. Additionally, an epigenetic marker of vascular aging (i.e., LINE-1 DNA methylation) was evaluated in human umbilical artery endothelial cells (HUAEC) from control and FGR subjects. Control guinea pig arteries showed an increased contractile response (KCl-induced) and a progressive impairment of NO-mediated relaxing responses as animals get older. FGR was associated with an initial preserved carotid artery reactivity as well as a later significant impairment in NO-mediated responses. Femoral arteries from FGR fetuses showed an increased contractility but a decreased relaxing response compared with control fetuses, and both responses were impaired in FGR-adults. Finally, FGR-HUAEC showed decreased LINE-1 DNA methylation compared with control-HUAEC. These data suggest that the aging of vascular function occurs by changes in NO-mediated responses, with limited alterations in contractile capacity. Further, these effects are accelerated and imposed at early stages of development in subjects exposed to a suboptimal intrauterine environment. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessArticle
In Vitro Entero-Capillary Barrier Exhibits Altered Inflammatory and Exosomal Communication Pattern after Exposure to Silica Nanoparticles
Int. J. Mol. Sci. 2019, 20(13), 3301; https://doi.org/10.3390/ijms20133301 - 05 Jul 2019
Abstract
The intestinal microvasculature (iMV) plays multiple pathogenic roles during chronic inflammatory bowel disease (IBD). The iMV acts as a second line of defense and is, among other factors, crucial for the innate immunity in the gut. It is also the therapeutic location in [...] Read more.
The intestinal microvasculature (iMV) plays multiple pathogenic roles during chronic inflammatory bowel disease (IBD). The iMV acts as a second line of defense and is, among other factors, crucial for the innate immunity in the gut. It is also the therapeutic location in IBD targeting aggravated leukocyte adhesion processes involving ICAM-1 and E-selectin. Specific targeting is stressed via nanoparticulate drug vehicles. Evaluating the iMV in enterocyte barrier models in vitro could shed light on inflammation and barrier-integrity processes during IBD. Therefore, we generated a barrier model by combining the enterocyte cell line Caco-2 with the microvascular endothelial cell line ISO-HAS-1 on opposite sides of a transwell filter-membrane under culture conditions which mimicked the physiological and inflamed conditions of IBD. The IBD model achieved a significant barrier-disruption, demonstrated via transepithelial-electrical resistance (TER), permeability-coefficient (Papp) and increase of sICAM sE-selectin and IL-8. In addition, the impact of a prospective model drug-vehicle (silica nanoparticles, aSNP) on ongoing inflammation was examined. A decrease of sICAM/sE-selectin was observed after aSNP-exposure to the inflamed endothelium. These findings correlated with a decreased secretion of ICAM/E-selectin bearing exosomes/microvesicles, as evaluated via ELISA. Our findings indicate that aSNP treatment of the inflamed endothelium during IBD may hamper exosomal/microvesicular systemic communication. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessArticle
Endothelial Colony Forming Cells as an Autologous Model to Study Endothelial Dysfunction in Patients with a Bicuspid Aortic Valve
Int. J. Mol. Sci. 2019, 20(13), 3251; https://doi.org/10.3390/ijms20133251 - 02 Jul 2019
Abstract
Bicuspid aortic valve (BAV), the most common congenital heart defect, is associated with an increased prevalence of aortic dilation, aortic rupture and aortic valve calcification. Endothelial cells (ECs) play a major role in vessel wall integrity. Little is known regarding EC function in [...] Read more.
Bicuspid aortic valve (BAV), the most common congenital heart defect, is associated with an increased prevalence of aortic dilation, aortic rupture and aortic valve calcification. Endothelial cells (ECs) play a major role in vessel wall integrity. Little is known regarding EC function in BAV patients due to lack of patient derived primary ECs. Endothelial colony forming cells (ECFCs) have been reported to be a valid surrogate model for several cardiovascular pathologies, thereby facilitating an in vitro system to assess patient-specific endothelial dysfunction. Therefore, the aim of this study was to investigate cellular functions in ECFCs isolated from BAV patients. Outgrowth and proliferation of ECFCs from patients with BAV (n = 34) and controls with a tricuspid aortic valve (TAV, n = 10) were determined and related to patient characteristics. Interestingly, we were only able to generate ECFCs from TAV and BAV patients without aortic dilation, and failed to isolate ECFC colonies from patients with a dilated aorta. Analyzing EC function showed that while proliferation, cell size and endothelial-to-mesenchymal transition were similar in TAV and BAV ECFCs, migration and the wound healing capacity of BAV ECFCs is significantly higher compared to TAV ECFCs. Furthermore, calcification is blunted in BAV compared to TAV ECFCs. Our results reveal ECs dysfunction in BAV patients and future research is required to unravel the underlying mechanisms and to further validate ECFCs as a patient-specific in vitro model for BAV. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessArticle
Photobiomodulation Enhances the Angiogenic Effect of Mesenchymal Stem Cells to Mitigate Radiation-Induced Enteropathy
Int. J. Mol. Sci. 2019, 20(5), 1131; https://doi.org/10.3390/ijms20051131 - 05 Mar 2019
Abstract
Radiation-induced enteropathy remains a major complication after accidental or therapeutic exposure to ionizing radiation. Recent evidence suggests that intestinal microvascular damage significantly affects the development of radiation enteropathy. Mesenchymal stem cell (MSC) therapy is a promising tool to regenerate various tissues, including skin [...] Read more.
Radiation-induced enteropathy remains a major complication after accidental or therapeutic exposure to ionizing radiation. Recent evidence suggests that intestinal microvascular damage significantly affects the development of radiation enteropathy. Mesenchymal stem cell (MSC) therapy is a promising tool to regenerate various tissues, including skin and intestine. Further, photobiomodulation (PBM), or low-level light therapy, can accelerate wound healing, especially by stimulating angiogenesis, and stem cells are particularly susceptible to PBM. Here, we explored the effect of PBM on the therapeutic potential of MSCs for the management of radiation enteropathy. In vitro, using human umbilical cord blood-derived MSCs, PBM increased proliferation and self-renewal. Intriguingly, the conditioned medium from MSCs treated with PBM attenuated irradiation-induced apoptosis and impaired tube formation in vascular endothelial cells, and these protective effects were associated with the upregulation of several angiogenic factors. In a mouse model of radiation-induced enteropathy, treatment with PBM-preconditioned MSCs alleviated mucosal destruction, improved crypt cell proliferation and epithelial barrier functions, and significantly attenuated the loss of microvascular endothelial cells in the irradiated intestinal mucosa. This treatment also significantly increased angiogenesis in the lamina propria. Together, we suggest that PBM enhances the angiogenic potential of MSCs, leading to improved therapeutic efficacy for the treatment of radiation-induced enteropathy. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessArticle
Plasma Dimethylarginine Levels and Carotid Intima–Media Thickness are related to Atrial Fibrillation in Patients with Embolic Stroke
Int. J. Mol. Sci. 2019, 20(3), 730; https://doi.org/10.3390/ijms20030730 - 09 Feb 2019
Cited by 2
Abstract
A relevant part of embolic strokes of undetermined source (ESUS) is assumed to be due to non-detected atrial fibrillation (AF). In this study, we aimed to investigate if markers of endothelial dysfunction and damage may indicate AF risk in embolic stroke. Eighty-eight patients [...] Read more.
A relevant part of embolic strokes of undetermined source (ESUS) is assumed to be due to non-detected atrial fibrillation (AF). In this study, we aimed to investigate if markers of endothelial dysfunction and damage may indicate AF risk in embolic stroke. Eighty-eight patients with ischemic stroke confirmed by imaging were assigned to one of three groups: ESUS, AF, or micro-/macroangiopathy. ESUS patients underwent prolonged Holter electrocardiography scheduled for three days. The National Institutes of Health Stroke Scale (NIHSS), the CHA2DS2VASC score, and the carotid intima–media thickness (CIMT) were obtained. Markers of endothelial (dys)function (L-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA)) were measured at day seven after stroke. ESUS patients were younger and had fewer cardiovascular risk factors than patients with determined stroke etiology. Compared with AF patients, ESUS patients showed significantly lower values of SDMA (p = 0.004) and higher values of L-arginine (p = 0.031), L-arginine/ADMA ratio (p = 0.006), L-arginine/SDMA ratio (p = 0.002), and ADMA/SDMA ratio (p = 0.013). Concordant differences could be observed comparing ESUS patients with those with newly diagnosed AF (p = 0.026; p = 0.03; p = 0.009; p = 0.004; and p = 0.046, respectively). CIMT was significantly larger in AF than in ESUS patients (p < 0.001), and was identified as an AF risk factor independent from CHA2DS2VASC in the regression analysis (p = 0.014). These findings may support future stratification for AF risk in patients who have suffered embolic stroke. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessCommunication
Unacylated Ghrelin Improves Vascular Dysfunction and Attenuates Atherosclerosis during High-Fat Diet Consumption in Rodents
Int. J. Mol. Sci. 2019, 20(3), 499; https://doi.org/10.3390/ijms20030499 - 24 Jan 2019
Cited by 1
Abstract
Unacylated ghrelin (UnGhr) exerts several beneficial actions on vascular function. The aim of this study was to assess the effects of UnGhr on high-fat induced endothelial dysfunction and its underlying mechanisms. Thoracic aortas from transgenic mice, which were overexpressing UnGhr and being control [...] Read more.
Unacylated ghrelin (UnGhr) exerts several beneficial actions on vascular function. The aim of this study was to assess the effects of UnGhr on high-fat induced endothelial dysfunction and its underlying mechanisms. Thoracic aortas from transgenic mice, which were overexpressing UnGhr and being control fed either a standard control diet (CD) or a high-fat diet (HFD) for 16 weeks, were harvested and used for the assessment of vascular reactivity, endothelial nitric oxide synthase (eNOS) expression and activity, thiobarbituric acid reactive substances (TBARS) and glutathione levels, and aortic lipid accumulation by Oil Red O staining. Relaxations due to acetylcholine and to DEA-NONOate were reduced (p < 0.05) in the HFD control aortas compared to vessels from the CD animals. Overexpression of UnGhr prevented HFD-induced vascular dysfunction, while eNOS expression and activity were similar in all vessels. HFD-induced vascular oxidative stress was demonstrated by increased (p < 0.05) aortic TBARS and glutathione in wild type (Wt) mice; however, this was not seen in UnGhr mice. Moreover, increased (p < 0.05) HFD-induced lipid accumulation in vessels from Wt mice was prevented by UnGhr overexpression. In conclusion, chronic UnGhr overexpression results in improved vascular function and reduced plaque formation through decreased vascular oxidative stress, without affecting the eNOS pathway. This research may provide new insight into the mechanisms underlying the beneficial effects of UnGhr on the vascular dysfunction associated with obesity and the metabolic syndrome. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Review

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Open AccessReview
Endothelial Dysfunction in Primary Aldosteronism
Int. J. Mol. Sci. 2019, 20(20), 5214; https://doi.org/10.3390/ijms20205214 - 21 Oct 2019
Abstract
Primary aldosteronism (PA) is characterized by excess production of aldosterone from the adrenal glands and is the most common and treatable cause of secondary hypertension. Aldosterone is a mineralocorticoid hormone that participates in the regulation of electrolyte balance, blood pressure, and tissue remodeling. [...] Read more.
Primary aldosteronism (PA) is characterized by excess production of aldosterone from the adrenal glands and is the most common and treatable cause of secondary hypertension. Aldosterone is a mineralocorticoid hormone that participates in the regulation of electrolyte balance, blood pressure, and tissue remodeling. The excess of aldosterone caused by PA results in an increase in cardiovascular and cerebrovascular complications, including coronary artery disease, myocardial infarction, stroke, transient ischemic attack, and even arrhythmia and heart failure. Endothelial dysfunction is a well-established fundamental cause of cardiovascular diseases and also a predictor of worse clinical outcomes. Accumulating evidence indicates that aldosterone plays an important role in the initiation and progression of endothelial dysfunction. Several mechanisms have been shown to contribute to aldosterone-induced endothelial dysfunction, including aldosterone-mediated vascular tone dysfunction, aldosterone- and endothelium-mediated vascular inflammation, aldosterone-related atherosclerosis, and vascular remodeling. These mechanisms are activated by aldosterone through genomic and nongenomic pathways in mineralocorticoid receptor-dependent and independent manners. In addition, other cells have also been shown to participate in these mechanisms. The complex interactions among endothelium, inflammatory cells, vascular smooth muscle cells and fibroblasts are crucial for aldosterone-mediated endothelial dysregulation. In this review, we discuss the association between aldosterone and endothelial function and the complex mechanisms from a molecular aspect. Furthermore, we also review current clinical research of endothelial dysfunction in patients with PA. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessReview
Molecular Characteristics and Treatment of Endothelial Dysfunction in Patients with COPD: A Review Article
Int. J. Mol. Sci. 2019, 20(18), 4329; https://doi.org/10.3390/ijms20184329 - 04 Sep 2019
Abstract
Patients with chronic obstructive pulmonary disease (COPD) show systemic consequences, such as chronic systemic inflammation leading to changes in the airway, airway penetrability, and endothelial function. Endothelial dysfunction is characterized by a list of alterations of endothelium towards reduced vasodilation, proinflammatory state, detachment [...] Read more.
Patients with chronic obstructive pulmonary disease (COPD) show systemic consequences, such as chronic systemic inflammation leading to changes in the airway, airway penetrability, and endothelial function. Endothelial dysfunction is characterized by a list of alterations of endothelium towards reduced vasodilation, proinflammatory state, detachment and apoptosis of endothelial cells, and development of atherosclerosis. COPD-induced endothelial dysfunction is associated with elevated cardiovascular risk. The increment of physical activities such as pulmonary rehabilitation (PR) training have a significant effect on COPD, thus, PR can be an integrative part of COPD treatment. In this narrative review the focus is on the function of endothelial inflammatory mediators [cytokines, chemokines, and cellular proteases] and pulmonary endothelial cells and endothelial dysfunction in COPD as well as the effects of dysfunction of the endothelium may play in COPD-related pulmonary hypertension. The relationship between smoking and endothelial dysfunction is also discussed. The connection between different pulmonary rehabilitation programs, arterial stiffness and pulse wave velocity (PWV) is presented. Endothelial dysfunction is a significant prognostic factor of COPD, which can be characterized by PWV. We discuss future considerations, like training programs, as an important part of the treatment that has a favorable impact on the endothelial function. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessReview
Cyclo-Oxygenase (COX) Inhibitors and Cardiovascular Risk: Are Non-Steroidal Anti-Inflammatory Drugs Really Anti-Inflammatory?
Int. J. Mol. Sci. 2019, 20(17), 4262; https://doi.org/10.3390/ijms20174262 - 30 Aug 2019
Abstract
Cyclo-oxygenase (COX) inhibitors are among the most commonly used drugs in the western world for their anti-inflammatory and analgesic effects. However, they are also well-known to increase the risk of coronary events. This area is of renewed significance given alarming new evidence suggesting [...] Read more.
Cyclo-oxygenase (COX) inhibitors are among the most commonly used drugs in the western world for their anti-inflammatory and analgesic effects. However, they are also well-known to increase the risk of coronary events. This area is of renewed significance given alarming new evidence suggesting this effect can occur even with acute usage. This contrasts with the well-established usage of aspirin as a mainstay for cardiovascular prophylaxis, as well as overwhelming evidence that COX inhibition induces vasodilation and is protective for vascular function. Here, we present an updated review of the preclinical and clinical literature regarding the cardiotoxicity of COX inhibitors. While studies to date have focussed on the role of COX in influencing renal and vascular function, we suggest an interaction between prostanoids and T cells may be a novel factor, mediating elevated cardiovascular disease risk with NSAID use. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessReview
Preeclampsia: Maternal Systemic Vascular Disorder Caused by Generalized Endothelial Dysfunction Due to Placental Antiangiogenic Factors
Int. J. Mol. Sci. 2019, 20(17), 4246; https://doi.org/10.3390/ijms20174246 - 30 Aug 2019
Abstract
Preeclampsia, a systemic vascular disorder characterized by new-onset hypertension and proteinuria after 20 weeks of gestation, is the leading cause of maternal and perinatal morbidity and mortality. Maternal endothelial dysfunction caused by placental factors has long been accepted with respect to the pathophysiology [...] Read more.
Preeclampsia, a systemic vascular disorder characterized by new-onset hypertension and proteinuria after 20 weeks of gestation, is the leading cause of maternal and perinatal morbidity and mortality. Maternal endothelial dysfunction caused by placental factors has long been accepted with respect to the pathophysiology of preeclampsia. Over the past decade, increased production of placental antiangiogenic factors has been identified as a placental factor leading to maternal endothelial dysfunction and systemic vascular dysfunction. This review summarizes the recent advances in understanding the molecular mechanisms of endothelial dysfunction caused by placental antiangiogenic factors, and the novel clinical strategies based on these discoveries. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessReview
Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?
Int. J. Mol. Sci. 2019, 20(15), 3775; https://doi.org/10.3390/ijms20153775 - 02 Aug 2019
Abstract
NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. [...] Read more.
NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessReview
Novel Biomarkers of Early Atherosclerotic Changes for Personalised Prevention of Cardiovascular Disease in Cervical Cancer and Human Papillomavirus Infection
Int. J. Mol. Sci. 2019, 20(15), 3720; https://doi.org/10.3390/ijms20153720 - 30 Jul 2019
Abstract
Cervical cancer is associated with a causative role of human papillomavirus (HPV), which is a highly prevalent infection. Recently, women with a genital HPV infection were found to have increased incidence of cardiovascular diseases (CVD), including severe cardiovascular events such as myocardial infarction [...] Read more.
Cervical cancer is associated with a causative role of human papillomavirus (HPV), which is a highly prevalent infection. Recently, women with a genital HPV infection were found to have increased incidence of cardiovascular diseases (CVD), including severe cardiovascular events such as myocardial infarction and stroke. The pathomechanisms of this relation are not yet fully understood, and may significantly affect the health of a large part of the population. Accelerated atherosclerosis is assumed to play a key role in the pathophysiology of this relationship. To identify high-risk groups of the population, it is necessary to stratify the CVD risk. Current algorithms, as widely used for the estimation of CVD risk, seem to be limited by the individual misclassification of high-risk subjects. However, personalised prediction of cardiovascular events is missing. Regarding HPV-related CVD, identification of novel sensitive biomarkers reflecting early atherosclerotic changes could be of major importance for such personalised cardiovascular risk prediction. Therefore, this review focuses on the pathomechanisms leading to HPV-related cardiovascular diseases with respect to atherosclerosis, and the description of potential novel biomarkers to detect the earliest atherosclerotic changes important for the prevention of CVD in HPV infection and cervical cancer. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessReview
Arterial Stiffness Assessed by Cardio-Ankle Vascular Index
Int. J. Mol. Sci. 2019, 20(15), 3664; https://doi.org/10.3390/ijms20153664 - 26 Jul 2019
Abstract
Arterial stiffness is an age-related disorder. In the medial layer of arteries, mechanical fracture due to fatigue failure for the pulsatile wall strain causes medial degeneration vascular remodeling. The alteration of extracellular matrix composition and arterial geometry result in structural arterial stiffness. Calcium [...] Read more.
Arterial stiffness is an age-related disorder. In the medial layer of arteries, mechanical fracture due to fatigue failure for the pulsatile wall strain causes medial degeneration vascular remodeling. The alteration of extracellular matrix composition and arterial geometry result in structural arterial stiffness. Calcium deposition and other factors such as advanced glycation end product-mediated collagen cross-linking aggravate the structural arterial stiffness. On the other hand, endothelial dysfunction is a cause of arterial stiffness. The biological molecular mechanisms relating to aging are known to involve the progression of arterial stiffness. Arterial stiffness further applies stress on large arteries and also microcirculation. Therefore, it is closely related to adverse outcomes in cardiovascular and cerebrovascular system. Cardio-ankle vascular index (CAVI) is a promising diagnostic tool for evaluating arterial stiffness. The principle is based on stiffness parameter β, which is an index intended to assess the distensibility of carotid artery. Stiffness parameter β is a two-dimensional technique obtained from changes of arterial diameter by pulse in one section. CAVI applied the stiffness parameter β to all of the arterial segments between heart and ankle using pulse wave velocity. CAVI has been commercially available for a decade and the clinical data of its effectiveness has accumulated. The characteristics of CAVI differ from other physiological tests of arterial stiffness due to the independency from blood pressure at the time of examination. This review describes the pathophysiology of arterial stiffness and CAVI. Molecular mechanisms will also be covered. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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The Role of Endothelial Dysfunction in Peripheral Blood Nerve Barrier: Molecular Mechanisms and Pathophysiological Implications
Int. J. Mol. Sci. 2019, 20(12), 3022; https://doi.org/10.3390/ijms20123022 - 20 Jun 2019
Cited by 2
Abstract
The exchange of solutes between the blood and the nerve tissue is mediated by specific and high selective barriers in order to ensure the integrity of the different compartments of the nervous system. At peripheral level, this function is maintained by the Blood [...] Read more.
The exchange of solutes between the blood and the nerve tissue is mediated by specific and high selective barriers in order to ensure the integrity of the different compartments of the nervous system. At peripheral level, this function is maintained by the Blood Nerve Barrier (BNB) that, in the presence, of specific stressor stimuli can be damaged causing the onset of neurodegenerative processes. An essential component of BNB is represented by the endothelial cells surrounding the sub-structures of peripheral nerves and increasing evidence suggests that endothelial dysfunction can be considered a leading cause of the nerve degeneration. The purpose of this review is to highlight the main mechanisms involved in the impairment of endothelial cells in specific diseases associated with peripheral nerve damage, such as diabetic neuropathy, erectile dysfunction and inflammation of the sciatic nerve. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Y Chromosome, Hypertension and Cardiovascular Disease: Is Inflammation the Answer?
Int. J. Mol. Sci. 2019, 20(12), 2892; https://doi.org/10.3390/ijms20122892 - 13 Jun 2019
Abstract
It is now becomingly increasingly evident that the functions of the mammalian Y chromosome are not circumscribed to the induction of male sex. While animal studies have shown variations in the Y are strongly accountable for blood pressure (BP), this is yet to [...] Read more.
It is now becomingly increasingly evident that the functions of the mammalian Y chromosome are not circumscribed to the induction of male sex. While animal studies have shown variations in the Y are strongly accountable for blood pressure (BP), this is yet to be confirmed in humans. We have recently shown modulation of adaptive immunity to be a significant mechanism underpinning Y-chromosome-dependent differences in BP in consomic strains. This is paralleled by studies in man showing Y chromosome haplogroup is a significant predictor for coronary artery disease through influencing pathways of immunity. Furthermore, recent studies in mice and humans have shown that Y chromosome lineage determines susceptibility to autoimmune disease. Here we review the evidence in animals and humans that Y chromosome lineage influences hypertension and cardiovascular disease risk, with a novel focus on pathways of immunity as a significant pathway involved. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessReview
The Role of Fibrinolytic Regulators in Vascular Dysfunction of Systemic Sclerosis
Int. J. Mol. Sci. 2019, 20(3), 619; https://doi.org/10.3390/ijms20030619 - 31 Jan 2019
Cited by 2
Abstract
Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by vascular dysfunction and extensive fibrosis of the skin and visceral organs. Vascular dysfunction is caused by endothelial cell (EC) apoptosis, defective angiogenesis, defective vasculogenesis, endothelial-to-mesenchymal transition (EndoMT), and coagulation abnormalities, [...] Read more.
Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by vascular dysfunction and extensive fibrosis of the skin and visceral organs. Vascular dysfunction is caused by endothelial cell (EC) apoptosis, defective angiogenesis, defective vasculogenesis, endothelial-to-mesenchymal transition (EndoMT), and coagulation abnormalities, and exacerbates the disease. Fibrinolytic regulators, such as plasminogen (Plg), plasmin, α2-antiplasmin (α2AP), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen activator inhibitor 1 (PAI-1), and angiostatin, are considered to play an important role in the maintenance of endothelial homeostasis, and are associated with the endothelial dysfunction of SSc. This review considers the roles of fibrinolytic factors in vascular dysfunction of SSc. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Endothelial Function: A Short Guide for the Interventional Cardiologist
Int. J. Mol. Sci. 2018, 19(12), 3838; https://doi.org/10.3390/ijms19123838 - 02 Dec 2018
Cited by 1
Abstract
An impaired function of the coronary endothelium is an important determinant of all stages of atherosclerosis, from initiation, to mediation of functional phenomena—such as spasm and plaque erosion, to atherothrombotic complications. Endothelial function is modified by therapies, including stent implantation. Finally, endothelial function [...] Read more.
An impaired function of the coronary endothelium is an important determinant of all stages of atherosclerosis, from initiation, to mediation of functional phenomena—such as spasm and plaque erosion, to atherothrombotic complications. Endothelial function is modified by therapies, including stent implantation. Finally, endothelial function changes over time, in response to physical stimuli and pharmocotherapies, and its assessment might provide information on how individual patients respond to specific therapies. In this review, we describe the role of the endothelium in the continuum of coronary atherosclerosis, from the perspective of the interventional cardiologist. In the first part, we review the current knowledge of the role of endothelial (dys)function on atherosclerotic plaque progression/instabilization and on the mechanisms of ischemia, in the absence of coronary artery stenosis. In the second part of this review, we describe the impact of coronary artery stenting on endothelial function, platelet aggregation, and inflammation. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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