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Vascular Biology and Endothelial Metabolism: From Physiology to Pathology

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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 (15 August 2023) | Viewed by 20329

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Special Issue Editors

Dr. Laura Locatelli

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Guest Editor

Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy
Interests: magnesium; endothelium; microfluidics; glucose; metabolism; mitochondria
Special Issues, Collections and Topics in MDPI journals

Dr. Maddalena Alessandra Wu

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Guest Editor

Division of Internal Medicine, Department of Biomedical and Clinical Sciences “Luigi Sacco”, Luigi Sacco Hospital, ASST Fatebenefratelli Sacco, University of Milan, Milan, Italy
Interests: endothelium; paroxysmal permeability disorders; idiopathic systemic capillary leak syndrome; angioedema; hypertension; venous thromboembolism; autonomic nervous system; COVID-19; myocarditis and pericarditis

Dr. Maria Bova

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Guest Editor

Department of Internal Medicine, AORN Cardarelli, Naples, Italy
Interests: hereditary angioedema with C1-inhibitor deficiency; bradykinin-mediated angioedema; angioedema with normal C1-inhibitor; orofacial granulomatosis; idiopathic angioedema
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The vascular system consists of arteries, veins and capillaries, three different types of blood vessels that together constitute an intricate network that maintains tissue homeostasis. Blood vessels not only deliver oxygen and nutrients to the tissues while removing waste, but also participate in different physiological processes.

The vascular wall is mainly composed of endothelial cells and smooth muscle cells, which cooperate in the development and homeostasis of the vessels.

Endothelial cells, which line the inner surfaces of blood vessels, play a fundamental role in orchestrating vascular functions and their dysfunction is demonstrated to be implicated in the onset of different cardiovascular diseases. Because a complex crosstalk occurs between endothelial cells and other cell types (bone, muscle and immune cells), endothelial dysfunction might affect the functions of virtually all the tissues. Smooth muscle cells are the principal component of the tunica media. Under physiological conditions, they exhibit a contractile phenotype, but can undergo trans-differentiation and acquire a synthetic phenotype.

Recently, attention has been drawn to the features of vascular metabolism in health and disease to individuate novel targets that pave the way to innovative treatments and countermeasures.

This Special Issue aims at providing an overview of the fields of basic and clinical vascular research, to obtain insights into the mechanisms that drive vascular cells to shift from physiological to pathological behaviour.

Dr. Laura Locatelli
Dr. Maddalena Alessandra Wu
Dr. Maria Bova
Guest Editors

Manuscript Submission Information

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.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

endothelium
smooth muscle cells
mitochondria
diabetes
cardiovascular disease
endothelial dysfunction
metabolism
vascular permeability
adhesion molecules

Published Papers (13 papers)

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17 pages, 3769 KiB

Open AccessArticle

Synergistic Interaction of 5-HT_1B and 5-HT_2B Receptors in Cytoplasmic Ca²⁺ Regulation in Human Umbilical Vein Endothelial Cells: Possible Involvement in Pathologies

by Elena Yu. Rybakova, Piotr P. Avdonin, Sergei K. Trufanov, Nikolay V. Goncharov and Pavel V. Avdonin

Int. J. Mol. Sci. 2023, 24(18), 13833; https://doi.org/10.3390/ijms241813833 - 8 Sep 2023

Cited by 1 | Viewed by 981

Abstract

The aim of this work was to explore the involvement of 5-HT_1B and 5-HT_2B receptors (5-HT_1BR and 5-HT_2BR) in the regulation of free cytoplasmic calcium concentration ([Ca²⁺]_i) in human umbilical vein endothelial cells (HUVEC). We have shown by quantitative PCR analysis, that 5-HT_1BR and 5-HT_2BR mRNAs levels are almost equal in HUVEC. Immunofluorescent staining demonstrated, that 5-HT_1BR and 5-HT_2BR are expressed both in plasma membrane and inside the cells. Intracellular 5-HT_1BR are localized mainly in the nuclear region, whereas 5-HT_2BR receptors are almost evenly distributed in HUVEC. 5-HT, 5-HT_1BR agonist CGS12066B, or 5-HT_2BR agonist BW723C86 added to HUVEC caused a slight increase in [Ca²⁺]_i, which was much lower than that of histamine, ATP, or SFLLRN, an agonist of protease-activated receptors (PAR1). However, activation of 5-HT_1BR with CGS12066B followed by activation of 5-HT_2BR with BW723C86 manifested a synergism of response, since several-fold higher rise in [Ca²⁺]_i occurred. CGS12066B caused more than a 5-fold increase in [Ca²⁺]_i rise in HUVEC in response to 5-HT. This 5-HT induced [Ca²⁺]_i rise was abolished by 5-HT_2BR antagonist RS127445, indicating that extracellular 5-HT acts through 5-HT_2BR. Synergistic [Ca²⁺]_i rise in response to activation of 5-HT1BR and 5-HT_2BR persisted in a calcium-free medium. It was suppressed by the phospholipase C inhibitor U73122 and was not inhibited by the ryanodine and NAADP receptors antagonists dantrolene and NED-19. [Ca²⁺]_i measurements in single cells demonstrated that activation of 5-HT_2BR alone by BW723C86 caused single asynchronous [Ca²⁺]_i oscillations in 19.8 ± 4.2% (n = 3) of HUVEC that occur with a long delay (66.1 ± 4.3 s, n = 71). On the contrary, histamine causes a simultaneous and almost immediate increase in [Ca²⁺]_i in all the cells. Pre-activation of 5-HT_1BR by CGS12066B led to a 3–4 fold increase in the number of HUVEC responding to BW723C86, to synchronization of their responses with a delay shortening, and to the bursts of [Ca²⁺]_i oscillations in addition to single oscillations. In conclusion, to get a full rise of [Ca²⁺]_i in HUVEC in response to 5-HT, simultaneous activation of 5-HT_1BR and 5-HT_2BR is required. 5-HT causes an increase in [Ca²⁺]_i via 5-HT_2BR while 5-HT_1BR could be activated by the membrane-permeable agonist CGS12066B. We hypothesized that CGS12066B acts via intracellular 5-HT_1BR inaccessible to extracellular 5-HT. Intracellular 5-HT_1BR might be activated by 5-HT which could be accumulated in EC under certain pathological conditions. Full article

(This article belongs to the Special Issue Vascular Biology and Endothelial Metabolism: From Physiology to Pathology)

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22 pages, 15572 KiB

Open AccessArticle

The Inhibition of the FGFR/PI3K/Akt Axis by AZD4547 Disrupts the Proangiogenic Microenvironment and Vasculogenic Mimicry Arising from the Interplay between Endothelial and Triple-Negative Breast Cancer Cells

by Gabriela Morales-Guadarrama, Edgar A. Méndez-Pérez, Janice García-Quiroz, Euclides Avila, María J. Ibarra-Sánchez, José Esparza-López, Rocío García-Becerra, Fernando Larrea and Lorenza Díaz

Int. J. Mol. Sci. 2023, 24(18), 13770; https://doi.org/10.3390/ijms241813770 - 6 Sep 2023

Viewed by 1303

Abstract

Vasculogenic mimicry (VM), a process in which aggressive cancer cells form tube-like structures, plays a crucial role in providing nutrients and escape routes. Highly plastic tumor cells, such as those with the triple-negative breast cancer (TNBC) phenotype, can develop VM. However, little is known about the interplay between the cellular components of the tumor microenvironment and TNBC cells’ VM capacity. In this study, we analyzed the ability of endothelial and stromal cells to induce VM when interacting with TNBC cells and analyzed the involvement of the FGFR/PI3K/Akt pathway in this process. VM was corroborated using fluorescently labeled TNBC cells. Only endothelial cells triggered VM formation, suggesting a predominant role of paracrine/juxtacrine factors from an endothelial origin in VM development. Via immunocytochemistry, qPCR, and secretome analyses, we determined an increased expression of proangiogenic factors as well as stemness markers in VM-forming cancer cells. Similarly, endothelial cells primed by TNBC cells showed an upregulation of proangiogenic molecules, including FGF, VEGFA, and several inflammatory cytokines. Endothelium-dependent TNBC-VM formation was prevented by AZD4547 or LY294002, strongly suggesting the involvement of the FGFR/PI3K/Akt axis in this process. Given that VM is associated with poor clinical prognosis, targeting FGFR/PI3K/Akt pharmacologically may hold promise for treating and preventing VM in TNBC tumors. Full article

(This article belongs to the Special Issue Vascular Biology and Endothelial Metabolism: From Physiology to Pathology)

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16 pages, 2623 KiB

Open AccessArticle

Changes in Adenosine Deaminase Activity and Endothelial Dysfunction after Mild Coronavirus Disease-2019

by Agata Jedrzejewska, Ada Kawecka, Alicja Braczko, Marzena Romanowska-Kocejko, Klaudia Stawarska, Milena Deptuła, Małgorzata Zawrzykraj, Marika Franczak, Oliwia Krol, Gabriela Harasim, Iga Walczak, Michał Pikuła, Marcin Hellmann and Barbara Kutryb-Zając

Int. J. Mol. Sci. 2023, 24(17), 13140; https://doi.org/10.3390/ijms241713140 - 24 Aug 2023

Cited by 2 | Viewed by 1135

Abstract

Endothelial cells are a preferential target for SARS-CoV-2 infection. Previously, we have reported that vascular adenosine deaminase 1 (ADA1) may serve as a biomarker of endothelial activation and vascular inflammation, while ADA2 plays a critical role in monocyte and macrophage function. In this study, we investigated the activities of circulating ADA isoenzymes in patients 8 weeks after mild COVID-19 and related them to the parameters of inflammation and microvascular/endothelial function. Post-COVID patients revealed microvascular dysfunction associated with the changes in circulating parameters of endothelial dysfunction and inflammatory activation. Interestingly, serum total ADA and ADA2 activities were diminished in post-COVID patients, while ADA1 remained unchanged in comparison to healthy controls without a prior diagnosis of SARS-CoV-2 infection. While serum ADA1 activity tended to positively correspond with the parameters of endothelial activation and inflammation, sICAM-1 and TNFα, serum ADA2 activity correlated with IL-10. Simultaneously, post-COVID patients had lower circulating levels of ADA1-anchoring protein, CD26, that may serve as an alternative receptor for virus binding. This suggests that after the infection CD26 is rather maintained in cell-attached form, enabling ADA1 complexing. This study points to the possible role of ADA isoenzymes in cardiovascular complications after mild COVID-19. Full article

(This article belongs to the Special Issue Vascular Biology and Endothelial Metabolism: From Physiology to Pathology)

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16 pages, 2329 KiB

Open AccessArticle

Decoding of miR-7-5p in Colony Forming Unit–Hill Colonies as a Biomarker of Subclinical Cardiovascular Disease—A MERIT Study

by Sherin Bakhashab, Hamzah Pratama Megantara, Dimas Kirana Mahaputra, Josie O’Neill, Jason Phowira and Jolanta U. Weaver

Int. J. Mol. Sci. 2023, 24(15), 11977; https://doi.org/10.3390/ijms241511977 - 26 Jul 2023

Cited by 1 | Viewed by 1189

Abstract

Colony forming unit–Hill (CFU–Hill) colonies were established to serve as a sensitive biomarker for vascular health. In animals, the overexpression of miR-7-5p was shown to be pro-atherogenic and associated with increased cardiovascular disease (CVD) risk. In a MERIT study, we aimed to explore the role of miR-7-5p expression in CFU–Hill colonies in type 1 diabetes mellitus (T1DM) and the effect of metformin in subclinical CVD. The expression of miR-7-5p in CFU–Hill colonies in 29 T1DM subjects without CVD and 20 healthy controls (HC) was measured. Metformin was administered to T1DM subjects for eight weeks. MiR-7-5p was upregulated in T1DM whereas metformin reduced it to HC levels. MiR-7-5p was positively correlated with c-reactive protein, and C-X-C motif chemokine ligand 10. The receiver operating characteristic curve revealed miR-7-5p as a biomarker of CVD, and upregulated miR-7-5p, defining subclinical CVD at a HbA1c level of 44.3 mmol/mol. Ingenuity pathway analysis predicted miR-7-5p to inhibit the mRNA expression of Krüppel-like factor 4, epidermal growth factor receptor, insulin-like growth factor 1 receptor, v-raf-1 murine leukemia viral oncogene homolog 1 and insulin receptor substrate ½, and insulin receptor, while metformin activated these miRNAs via transforming growth factor-β1 and Smad2/3. We proved the pro-atherogenic effect of miR-7-5p that maybe used as a prognostic biomarker. Full article

(This article belongs to the Special Issue Vascular Biology and Endothelial Metabolism: From Physiology to Pathology)

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15 pages, 3689 KiB

Open AccessArticle

Red Blood Cells and Endothelium Derived Circulating Extracellular Vesicles in Health and Chronic Heart Failure: A Focus on Phosphatidylserine Dynamics in Vesiculation

by Rosa Suades, Alba Vilella-Figuerola, Teresa Padró, Sonia Mirabet and Lina Badimon

Int. J. Mol. Sci. 2023, 24(14), 11824; https://doi.org/10.3390/ijms241411824 - 23 Jul 2023

Cited by 1 | Viewed by 1036

Abstract

Circulating extracellular microvesicles (cEVs) are characterised by presenting surface antigens of parental cells. Since their biogenesis involves the translocation of phosphatidylserine (PS) from the inner to the outer leaflet of the plasma membrane, exposed PS has been considered as a recognition hallmark of cEVs. However, not all cEVs externalise PS. In this study, we have phenotypically and quantitatively characterised cEVs by flow cytometry, paying special attention to the proportions of PS in chronic heart failure patients (cHF; n = 119) and a reference non-HF group (n = 21). PS⁻-cEVs were predominantly found in both groups. Parental markers showed differential pattern depending on the PS exposure. Endothelium-derived and connexin 43-rich cEVs were mainly PS⁻-cEVs and significantly increased in cHF. On the contrary, platelet-derived cEVs were mostly PS⁺ and were increased in the non-HF group. We observed similar levels of PS⁺- and PS⁻-cEVs in non-HF subjects when analysing immune cell-derived Evs, but there was a subset-specific difference in cHF patients. Indeed, those cEVs carrying CD45⁺, CD29⁺, CD11b⁺, and CD15⁺ were mainly PS⁺-cEVs, while those carrying CD14⁺, CD3⁺, and CD56⁺ were mainly PS⁻-cEVs. In conclusion, endothelial and red blood cells are stressed in cHF patients, as detected by a high shedding of cEVs. Despite PS⁺-cEVs and PS⁻-cEVs representing two distinct cEV populations, their release and potential function as both biomarkers and shuttles for cell communication seem unrelated to their PS content. Full article

(This article belongs to the Special Issue Vascular Biology and Endothelial Metabolism: From Physiology to Pathology)

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9 pages, 1401 KiB

Open AccessCommunication

Bortezomib Increased Vascular Permeability by Decreasing Cell–Cell Junction Molecules in Human Pulmonary Microvascular Endothelial Cells

by Taichi Matsumoto, Junichi Matsumoto, Yuka Matsushita, Moeno Arimura, Kentaro Aono, Mikiko Aoki, Kazuki Terada, Masayoshi Mori, Yutaka Haramaki, Takuya Imatoh, Atsushi Yamauchi and Keisuke Migita

Int. J. Mol. Sci. 2023, 24(13), 10842; https://doi.org/10.3390/ijms241310842 - 29 Jun 2023

Cited by 1 | Viewed by 1053

Abstract

Bortezomib (BTZ), a chemotherapeutic drug used to treat multiple myeloma, induces life-threatening side effects, including severe pulmonary toxicity. However, the mechanisms underlying these effects remain unclear. The objectives of this study were to (1) investigate whether BTZ influences vascular permeability and (2) clarify the effect of BTZ on the expression of molecules associated with cell–cell junctions using human pulmonary microvascular endothelial cells in vitro. Clinically relevant concentrations of BTZ induced limited cytotoxicity and increased the permeability of human pulmonary microvascular endothelial cell monolayers. BTZ decreased the protein expression of claudin-5, occludin, and VE-cadherin but not that of ZO-1 and β-catenin. Additionally, BTZ decreased the mRNA expression of claudin-5, occludin, ZO-1, VE-cadherin, and β-catenin. Our results suggest that BTZ increases the vascular permeability of the pulmonary microvascular endothelium by downregulating cell–cell junction molecules, particularly claudin-5, occludin, and VE-cadherin. Full article

(This article belongs to the Special Issue Vascular Biology and Endothelial Metabolism: From Physiology to Pathology)

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20 pages, 3562 KiB

Open AccessArticle

Intersection of Coagulation and Fibrinolysis by the Glycosylphosphatidylinositol (GPI)-Anchored Serine Protease Testisin

by Marguerite S. Buzza, Nisha R. Pawar, Amando A. Strong and Toni M. Antalis

Int. J. Mol. Sci. 2023, 24(11), 9306; https://doi.org/10.3390/ijms24119306 - 26 May 2023

Cited by 1 | Viewed by 1201

Abstract

Hemostasis is a delicate balance between coagulation and fibrinolysis that regulates the formation and removal of fibrin, respectively. Positive and negative feedback loops and crosstalk between coagulation and fibrinolytic serine proteases maintain the hemostatic balance to prevent both excessive bleeding and thrombosis. Here, we identify a novel role for the glycosylphosphatidylinositol (GPI)-anchored serine protease testisin in the regulation of pericellular hemostasis. Using in vitro cell-based fibrin generation assays, we found that the expression of catalytically active testisin on the cell surface accelerates thrombin-dependent fibrin polymerization, and intriguingly, that it subsequently promotes accelerated fibrinolysis. We find that the testisin-dependent fibrin formation is inhibited by rivaroxaban, a specific inhibitor of the central prothrombin-activating serine protease factor Xa (FXa), demonstrating that cell-surface testisin acts upstream of factor X (FX) to promote fibrin formation at the cell surface. Unexpectedly, testisin was also found to accelerate fibrinolysis by stimulating the plasmin-dependent degradation of fibrin and enhancing plasmin-dependent cell invasion through polymerized fibrin. Testisin was not a direct activator of plasminogen, but it is able to induce zymogen cleavage and the activation of pro-urokinase plasminogen activator (pro-uPA), which converts plasminogen to plasmin. These data identify a new proteolytic component that can regulate pericellular hemostatic cascades at the cell surface, which has implications for angiogenesis, cancer biology, and male fertility. Full article

(This article belongs to the Special Issue Vascular Biology and Endothelial Metabolism: From Physiology to Pathology)

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15 pages, 4183 KiB

Open AccessArticle

Cooperation of Complement MASP-1 with Other Proinflammatory Factors to Enhance the Activation of Endothelial Cells

by Zsuzsanna Németh, Márta L. Debreczeni, Erika Kajdácsi, József Dobó, Péter Gál and László Cervenak

Int. J. Mol. Sci. 2023, 24(11), 9181; https://doi.org/10.3390/ijms24119181 - 24 May 2023

Cited by 2 | Viewed by 1223

Abstract

Endothelial cells play an important role in sensing danger signals and regulating inflammation. Several factors are capable of inducing a proinflammatory response (e.g., LPS, histamine, IFNγ, and bradykinin), and these factors act simultaneously during the natural course of the inflammatory reaction. We have previously shown that the complement protein mannan-binding lectin-associated serine protease-1 (MASP-1) also induces a proinflammatory activation of the endothelial cells. Our aim was to investigate the possible cooperation between MASP-1 and other proinflammatory mediators when they are present in low doses. We used HUVECs and measured Ca²⁺ mobilization, IL-8, E-selectin, VCAM-1 expression, endothelial permeability, and mRNA levels of specific receptors. LPS pretreatment increased the expression of PAR2, a MASP-1 receptor, and furthermore, MASP-1 and LPS enhanced each other’s effects in regulating IL-8, E-selectin, Ca²⁺ mobilization, and changes in permeability in a variety of ways. Cotreatment of MASP-1 and IFNγ increased the IL-8 expression of HUVECs. MASP-1 induced bradykinin and histamine receptor expression, and consequently, increased Ca²⁺ mobilization was found. Pretreatment with IFNγ enhanced MASP-1-induced Ca²⁺ mobilization. Our findings highlight that well-known proinflammatory mediators and MASP-1, even at low effective doses, can strongly synergize to enhance the inflammatory response of endothelial cells. Full article

(This article belongs to the Special Issue Vascular Biology and Endothelial Metabolism: From Physiology to Pathology)

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16 pages, 779 KiB

Open AccessArticle

The Role of Nitric Oxide in the Micro- and Macrovascular Response to a 7-Day High-Salt Diet in Healthy Individuals

by Ivana Tolj, Ana Stupin, Ines Drenjančević, Petar Šušnjara, Leon Perić and Marko Stupin

Int. J. Mol. Sci. 2023, 24(8), 7157; https://doi.org/10.3390/ijms24087157 - 12 Apr 2023

Cited by 1 | Viewed by 1207

Abstract

This study aimed to investigate the specific role of nitric oxide (NO) in micro- and macrovascular response to a 7-day high-salt (HS) diet, specifically by measuring skin microvascular local thermal hyperemia and the flow-mediated dilation of the brachial artery, as well as serum NO and three NO synthase enzyme (NOS) isoform concentrations in healthy individuals. It also aimed to examine the concept of non-osmotic sodium storage in the skin following the HS diet by measuring body fluid status and systemic hemodynamic responses, as well as serum vascular endothelial growth factor C (VEGF-C) concentration. Forty-six young, healthy individuals completed a 7-day low-salt diet, followed by a 7-day HS diet protocol. The 7-day HS diet resulted in impaired NO-mediated endothelial vasodilation in peripheral microcirculation and conduit arteries, in increased eNOS, decreased nNOS, and unchanged iNOS concentration and NO serum level. The HS diet did not change the volume of interstitial fluid, the systemic vascular resistance or the VEGF-C serum level. These results indicate that the 7-day HS-diet induces systemic impairment of NO-mediated endothelial vasodilation, while dissociation in the eNOS and nNOS response indicates complex adaptation of main NO-generating enzyme isoforms to HS intake in healthy individuals. Our results failed to support the concept of non-osmotic sodium storage. Full article

(This article belongs to the Special Issue Vascular Biology and Endothelial Metabolism: From Physiology to Pathology)

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20 pages, 3698 KiB

Open AccessArticle

MicroRNA-423-5p Mediates Cocaine-Induced Smooth Muscle Cell Contraction by Targeting Cacna2d2

by Derek M. Dykxhoorn, Huilan Wang, Andrea Da Fonseca Ferreira, Jianqin Wei and Chunming Dong

Int. J. Mol. Sci. 2023, 24(7), 6584; https://doi.org/10.3390/ijms24076584 - 1 Apr 2023

Cited by 1 | Viewed by 1780

Abstract

Cocaine abuse increases the risk of atherosclerotic cardiovascular disease (CVD) and causes acute coronary syndromes (ACS) and hypertension (HTN). Significant research has explored the role of the sympathetic nervous system mediating the cocaine effects on the cardiovascular (CV) system. However, the response of the sympathetic nervous system alone is insufficient to completely account for the CV consequences seen in cocaine users. In this study, we examined the role of microRNAs (miRNAs) in mediating the effect of cocaine on the CV system. MiRNAs regulate many important biological processes and have been associated with both response to cocaine and CV disease development. Multiple miRNAs have altered expression in the CV system (CVS) upon cocaine exposure. To understand the molecular mechanisms underlying the cocaine response in the CV system, we studied the role of miRNA-423-5p and its target Cacna2d2 in the regulation of intracellular calcium concentration and SMC contractility, a critical factor in the modulation of blood pressure (BP). We used in vivo models to evaluate BP and aortic stiffness. In vitro, cocaine treatment decreased miR-423-5p expression and increased Cacna2d2 expression, which led to elevated intracellular calcium concentrations and increased SMC contractility. Overexpression of miR-423-5p, silencing of its target Cacna2d2, and treatment with a calcium channel blocker reversed the elevated SMC contractility caused by cocaine. In contrast, suppression of miR-423-5p increased the intracellular calcium concentration and SMC contractibility. In vivo, smooth muscle-specific overexpression of miR-423-5p ameliorated the increase in BP and aortic stiffness associated with cocaine use. Thus, miR-423-5p regulates SMC contraction by modulating Cacna2d2 expression increasing intracellular calcium concentrations. Modulation of the miR-423-5p—Cacna2d2—Calcium transport pathway may represent a novel therapeutic strategy to improve cocaine-induced HTN and aortic stiffness. Full article

(This article belongs to the Special Issue Vascular Biology and Endothelial Metabolism: From Physiology to Pathology)

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15 pages, 2952 KiB

Open AccessArticle

Protective Effect of Ergothioneine against 7-Ketocholesterol-Induced Mitochondrial Damage in hCMEC/D3 Human Brain Endothelial Cells

by Damien Meng-Kiat Leow, Irwin Kee-Mun Cheah, Zachary Wei-Jie Fong, Barry Halliwell and Wei-Yi Ong

Int. J. Mol. Sci. 2023, 24(6), 5498; https://doi.org/10.3390/ijms24065498 - 13 Mar 2023

Cited by 2 | Viewed by 2284

Abstract

Recent findings have suggested that the natural compound ergothioneine (ET), which is synthesised by certain fungi and bacteria, has considerable cytoprotective potential. We previously demonstrated the anti-inflammatory effects of ET on 7-ketocholesterol (7KC)-induced endothelial injury in human blood-brain barrier endothelial cells (hCMEC/D3). 7KC is an oxidised form of cholesterol present in atheromatous plaques and the sera of patients with hypercholesterolaemia and diabetes mellitus. The aim of this study was to elucidate the protective effect of ET on 7KC-induced mitochondrial damage. Exposure of human brain endothelial cells to 7KC led to a loss of cell viability, together with an increase in intracellular free calcium levels, increased cellular and mitochondrial reactive oxygen species, a decrease in mitochondrial membrane potential, reductions in ATP levels, and increases in mRNA expression of TFAM, Nrf2, IL-1β, IL-6 and IL-8. These effects were significantly decreased by ET. Protective effects of ET were diminished when endothelial cells were coincubated with verapamil hydrochloride (VHCL), a nonspecific inhibitor of the ET transporter OCTN1 (SLC22A4). This outcome demonstrates that ET-mediated protection against 7KC-induced mitochondrial damage occurred intracellularly and not through direct interaction with 7KC. OCTN1 mRNA expression itself was significantly increased in endothelial cells after 7KC treatment, consistent with the notion that stress and injury may increase ET uptake. Our results indicate that ET can protect against 7KC-induced mitochondrial injury in brain endothelial cells. Full article

(This article belongs to the Special Issue Vascular Biology and Endothelial Metabolism: From Physiology to Pathology)

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Review

Jump to: Research

26 pages, 1638 KiB

Open AccessReview

Endothelin-1 in Health and Disease

by Katherine M. R. M. Banecki and Kim A. Dora

Int. J. Mol. Sci. 2023, 24(14), 11295; https://doi.org/10.3390/ijms241411295 - 10 Jul 2023

Cited by 6 | Viewed by 3242

Abstract

Discovered almost 40 years ago, the potent vasoconstrictor peptide endothelin-1 (ET-1) has a wide range of roles both physiologically and pathologically. In recent years, there has been a focus on the contribution of ET-1 to disease. This has led to the development of various ET receptor antagonists, some of which are approved for the treatment of pulmonary arterial hypertension, while clinical trials for other diseases have been numerous yet, for the most part, unsuccessful. However, given the vast physiological impact of ET-1, it is both surprising and disappointing that therapeutics targeting the ET-1 pathway remain limited. Strategies aimed at the pathways influencing the synthesis and release of ET-1 could provide new therapeutic avenues, yet research using cultured cells in vitro has had little follow up in intact ex vivo and in vivo preparations. This article summarises what is currently known about the synthesis, storage and release of ET-1 as well as the role of ET-1 in several diseases including cardiovascular diseases, COVID-19 and chronic pain. Unravelling the ET-1 pathway and identifying therapeutic targets has the potential to treat many diseases whether through disease prevention, slowing disease progression or reversing pathology. Full article

(This article belongs to the Special Issue Vascular Biology and Endothelial Metabolism: From Physiology to Pathology)

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15 pages, 1360 KiB

Open AccessReview

Non-Haemodynamic Mechanisms Underlying Hypertension-Associated Damage in Target Kidney Components

by Elisa Russo, Elisabetta Bussalino, Lucia Macciò, Daniela Verzola, Michela Saio, Pasquale Esposito, Giovanna Leoncini, Roberto Pontremoli and Francesca Viazzi

Int. J. Mol. Sci. 2023, 24(11), 9422; https://doi.org/10.3390/ijms24119422 - 29 May 2023

Cited by 4 | Viewed by 1774

Abstract

Arterial hypertension (AH) is a global challenge that greatly impacts cardiovascular morbidity and mortality worldwide. AH is a major risk factor for the development and progression of kidney disease. Several antihypertensive treatment options are already available to counteract the progression of kidney disease. Despite the implementation of the clinical use of renin–angiotensin aldosterone system (RAAS) inhibitors, gliflozins, endothelin receptor antagonists, and their combination, the kidney damage associated with AH is far from being resolved. Fortunately, recent studies on the molecular mechanisms of AH-induced kidney damage have identified novel potential therapeutic targets. Several pathophysiologic pathways have been shown to play a key role in AH-induced kidney damage, including inappropriate tissue activation of the RAAS and immunity system, leading to oxidative stress and inflammation. Moreover, the intracellular effects of increased uric acid and cell phenotype transition showed their link with changes in kidney structure in the early phase of AH. Emerging therapies targeting novel disease mechanisms could provide powerful approaches for hypertensive nephropathy management in the future. In this review, we would like to focus on the interactions of pathways linking the molecular consequences of AH to kidney damage, suggesting how old and new therapies could aim to protect the kidney. Full article

(This article belongs to the Special Issue Vascular Biology and Endothelial Metabolism: From Physiology to Pathology)

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