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Advances in Endothelial Cell Biology

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 (31 May 2021) | Viewed by 67970

Special Issue Editor

Dr. Béatrice Charreau

E-Mail Website
Guest Editor
Centre de Recherche en Transplantation et Immunologie (CRTI) INSERM UMR1064, Université de Nantes, 44093 Nantes, France
Interests: endothelial cell biology; transplantation immunology; innate immunity; CD8 T cells; infection; HCMV; inflammation; cell signaling; biomarkers; MHC; antibodies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

At the interface between the blood and tissues, the endothelium lining blood vessels is a gatekeeper of vascular barrier integrity that ensures adequate tissue homeostasis and cell trafficking. Consequently, endothelial cells (ECs) display a large panel of key regulatory functions to control vascular tone, blood coagulation and fibrinolysis, complement activation, leucocyte migration, inflammation, and innate and adaptive immunity. These functions result from the fine-tuned expression of specific surface molecules as well as the release of soluble mediators. Transient EC activation may occur after a perturbation, such as an inflammatory stimulus, and is characterized by the acquisition of new cellular functions to restore homeostasis. The activation of the NF-κB, PI3K, and MAPK pathways plays a role in both the tightly controlled transcription of the genes that feature the activated EC phenotype and functions and the return to a resting state. The characteristics and functions of ECs may vary according to the nature of the vessel and tissue, reflecting the heterogeneity of ECs. ECs display selective and bidirectional crosstalks with other cell types, including hematopoietic and immune cells, that influence cell differentiation, activation, and migration. For instance, the TGFβ and Notch signaling pathways are key players orchestrating the bidirectional interplay between ECs and macrophages involved in macrophage polarization, endothelial-to-mesenchymal transition, and graft endothelialization. Endothelial cell-specific biomarkers may provide useful tools for non-invasive investigations of vascular injury in patients. Selective therapeutic approaches targeting ECs are needed to protect ECs from injury, restore vascular integrity, promote re-endothelialization and reparative neoangiogenesis, and, in contrast, avoid excessive proliferation and angiogenesis, such as in tumors. This requires both the identification of endothelium-specific molecular targets and the development of dedicated experimental models for the screening of new drugs or biotherapies.

The main aim of this Special Issue is to provide an overview of recent investigations in the field of endothelial cell biology that advance our understanding of the molecular mechanisms that trigger normal EC functions and dysfunctions in pathologies and demonstrate how better knowledge of EC biology may lead to the discovery of novel molecular diagnostic technologies and targeted therapeutics.

Topics of interest to this Special Issue include, but are not limited to:

  • endothelial biomarkers for screening and diagnosis;
  • endothelial targets for immunotherapy;
  • molecular crosstalks between endothelial cells and other cells;
  • endothelial cell biology and immunity;
  • mediators of endothelial cell dysfunction;
  • molecular markers of endothelial cell heterogeneity;
  • endothelial cell signaling in cell communication;
  • endothelial cells as cell targets for drug design;
  • transcriptomics, epigenomics, and metabolomics in endothelial cells;
  • non-coding RNAs in endothelial cells;
  • endothelial cells and virus receptors;
  • molecular determinants of endothelial cell plasticity; and
  • shedding of endothelial proteins and release of extracellular vesicles.

Dr. Béatrice Charreau
Guest Editor

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

  • angiogenesis
  • apoptosis
  • biomarkers
  • cellular communication
  • drug screening
  • endothelial cells
  • endothelial dysfunction
  • endothelium targeted therapy
  • immunity
  • inflammation
  • intracellular signaling
  • molecular diagnostics
  • Notch signaling
  • non-coding RNAs
  • omics
  • receptor molecules
  • signaling pathways
  • SNP genotyping
  • vascular disorders
  • therapeutic targets

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Published Papers (20 papers)

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Editorial

Jump to: Research, Review

4 pages, 212 KiB  
Editorial
Advances in Endothelial Cell Biology: From Knowledge to Control
by Béatrice Charreau
Int. J. Mol. Sci. 2022, 23(12), 6403; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126403 - 08 Jun 2022
Cited by 3 | Viewed by 1175
Abstract
The aim of this Special Issue is to provide an overview of recent investigations in the field of endothelial cell (EC) biology that advance our understanding of the molecular mechanisms that trigger normal EC functions and dysfunctions in pathologies and to demonstrate how [...] Read more.
The aim of this Special Issue is to provide an overview of recent investigations in the field of endothelial cell (EC) biology that advance our understanding of the molecular mechanisms that trigger normal EC functions and dysfunctions in pathologies and to demonstrate how improved knowledge of EC biology may lead to the discovery of novel molecular diagnostic technologies and targeted therapeutics [...] Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)

Research

Jump to: Editorial, Review

19 pages, 3049 KiB  
Article
Pleiotropic, Unique and Shared Responses Elicited by IL-6 Family Cytokines in Human Vascular Endothelial Cells
by Madelene Lindkvist, Mulugeta M. Zegeye, Magnus Grenegård and Liza U. Ljungberg
Int. J. Mol. Sci. 2022, 23(3), 1448; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031448 - 27 Jan 2022
Cited by 7 | Viewed by 2437
Abstract
Vascular endothelial cells express glycoprotein 130 (gp130), which is utilized as a signaling receptor by cytokines in the interleukin-6 (IL-6) family. Several IL-6 family cytokines can be found in the circulatory system during physiological or pathological conditions, and may influence endothelial function and [...] Read more.
Vascular endothelial cells express glycoprotein 130 (gp130), which is utilized as a signaling receptor by cytokines in the interleukin-6 (IL-6) family. Several IL-6 family cytokines can be found in the circulatory system during physiological or pathological conditions, and may influence endothelial function and response. This study evaluated and compared the cellular and molecular responses induced by IL-6 family cytokines in human endothelial cells. A proteomic analysis showed that IL-6 family cytokines induce the release of a range of proteins from endothelial cells, such as C-C motif chemokine ligand 23, hepatocyte growth factor, and IL-6. Pathway analysis indicated that gp130-signaling in endothelial cells regulates several functions related to angiogenesis and immune cell recruitment. The present investigation also disclosed differences and similarities between different IL-6 family cytokines in their ability to induce protein release and regulate gene expression and intracellular signaling, in regards to which oncostatin M showed the most pronounced effect. Further, this study showed that soluble gp130 preferentially blocks trans-signaling-induced responses, but does not affect responses induced by classic signaling. In conclusion, IL-6 family cytokines induce both specific and overlapping molecular responses in endothelial cells, and regulate genes and proteins involved in angiogenesis and immune cell recruitment. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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20 pages, 3749 KiB  
Article
Cell-Free Hemoglobin Does Not Attenuate the Effects of SARS-CoV-2 Spike Protein S1 Subunit in Pulmonary Endothelial Cells
by Sirsendu Jana, Michael R. Heaven and Abdu I. Alayash
Int. J. Mol. Sci. 2021, 22(16), 9041; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22169041 - 22 Aug 2021
Cited by 14 | Viewed by 2876
Abstract
SARS-CoV-2 primarily infects epithelial airway cells that express the host entry receptor angiotensin-converting enzyme 2 (ACE2), which binds to the S1 spike protein on the surface of the virus. To delineate the impact of S1 spike protein interaction with the ACE2 receptor, we [...] Read more.
SARS-CoV-2 primarily infects epithelial airway cells that express the host entry receptor angiotensin-converting enzyme 2 (ACE2), which binds to the S1 spike protein on the surface of the virus. To delineate the impact of S1 spike protein interaction with the ACE2 receptor, we incubated the S1 spike protein with human pulmonary arterial endothelial cells (HPAEC). HPAEC treatment with the S1 spike protein caused disruption of endothelial barrier function, increased levels of numerous inflammatory molecules (VCAM-1, ICAM-1, IL-1β, CCL5, CXCL10), elevated mitochondrial reactive oxygen species (ROS), and a mild rise in glycolytic reserve capacity. Because low oxygen tension (hypoxia) is associated with severe cases of COVID-19, we also evaluated treatment with hemoglobin (HbA) as a potential countermeasure in hypoxic and normal oxygen environments in analyses with the S1 spike protein. We found hypoxia downregulated the expression of the ACE2 receptor and increased the critical oxygen homeostatic signaling protein, hypoxia-inducible factor (HIF-1α); however, treatment of the cells with HbA yielded no apparent change in the levels of ACE2 or HIF-1α. Use of quantitative proteomics revealed that S1 spike protein-treated cells have few differentially regulated proteins in hypoxic conditions, consistent with the finding that ACE2 serves as the host viral receptor and is reduced in hypoxia. However, in normoxic conditions, we found perturbed abundance of proteins in signaling pathways related to lysosomes, extracellular matrix receptor interaction, focal adhesion, and pyrimidine metabolism. We conclude that the spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in HPAEC, and that treatment with HbA failed to reverse the vast majority of these spike protein-induced changes. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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18 pages, 2453 KiB  
Article
Thrombin Inhibition Prevents Endothelial Dysfunction and Reverses 20-HETE Overproduction without Affecting Blood Pressure in Angiotensin II-Induced Hypertension in Mice
by Agnieszka Kij, Anna Bar, Kamil Przyborowski, Bartosz Proniewski, Lukasz Mateuszuk, Agnieszka Jasztal, Anna Kieronska-Rudek, Brygida Marczyk, Karolina Matyjaszczyk-Gwarda, Anna Tworzydlo, Camilla Enggaard, Pernille B. Lærkegaard Hansen, Boye Jensen, Maria Walczak and Stefan Chlopicki
Int. J. Mol. Sci. 2021, 22(16), 8664; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168664 - 12 Aug 2021
Cited by 4 | Viewed by 2761
Abstract
Angiotensin II (Ang II) induces hypertension and endothelial dysfunction, but the involvement of thrombin in these responses is not clear. Here, we assessed the effects of the inhibition of thrombin activity by dabigatran on Ang II-induced hypertension and endothelial dysfunction in mice with [...] Read more.
Angiotensin II (Ang II) induces hypertension and endothelial dysfunction, but the involvement of thrombin in these responses is not clear. Here, we assessed the effects of the inhibition of thrombin activity by dabigatran on Ang II-induced hypertension and endothelial dysfunction in mice with a particular focus on NO- and 20-HETE-dependent pathways. As expected, dabigatran administration significantly delayed thrombin generation (CAT assay) in Ang II-treated hypertensive mice, and interestingly, it prevented endothelial dysfunction development, but it did not affect elevated blood pressure nor excessive aortic wall thickening. Dabigatran’s effects on endothelial function in Ang II-treated mice were evidenced by improved NO-dependent relaxation in the aorta in response to acetylcholine in vivo (MRI measurements) and increased systemic NO bioavailability (NO2− quantification) with a concomitant increased ex vivo production of endothelium-derived NO (EPR analysis). Dabigatran treatment also contributed to the reduction in the endothelial expression of pro-inflammatory vWF and ICAM-1. Interestingly, the fall in systemic NO bioavailability in Ang II-treated mice was associated with increased 20-HETE concentration in plasma (UPLC-MS/MS analysis), which was normalised by dabigatran treatment. Taking together, the inhibition of thrombin activity in Ang II-induced hypertension in mice improves the NO-dependent function of vascular endothelium and normalises the 20-HETE-depedent pathway without affecting the blood pressure and vascular remodelling. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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14 pages, 5511 KiB  
Article
LncRNA AERRIE Is Required for Sulfatase 1 Expression, but Not for Endothelial-to-Mesenchymal Transition
by Tan Phát Pham, Anke S. van Bergen, Veerle Kremer, Simone F. Glaser, Stefanie Dimmeler and Reinier A. Boon
Int. J. Mol. Sci. 2021, 22(15), 8088; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158088 - 28 Jul 2021
Cited by 3 | Viewed by 2095
Abstract
Endothelial cells can acquire a mesenchymal phenotype through a process called Endothelial-to-Mesenchymal transition (EndMT). This event is found in embryonic development, but also in pathological conditions. Blood vessels lose their ability to maintain vascular homeostasis and ultimately develop atherosclerosis, pulmonary hypertension, or fibrosis. [...] Read more.
Endothelial cells can acquire a mesenchymal phenotype through a process called Endothelial-to-Mesenchymal transition (EndMT). This event is found in embryonic development, but also in pathological conditions. Blood vessels lose their ability to maintain vascular homeostasis and ultimately develop atherosclerosis, pulmonary hypertension, or fibrosis. An increase in inflammatory signals causes an upregulation of EndMT transcription factors, mesenchymal markers, and a decrease in endothelial markers. In our study, we show that the induction of EndMT results in an increase in long non-coding RNA AERRIE expression. JMJD2B, a known EndMT regulator, induces AERRIE and subsequently SULF1. Silencing of AERRIE shows a partial regulation of SULF1 but showed no effect on the endothelial and mesenchymal markers. Additionally, the overexpression of AERRIE results in no significant changes in EndMT markers, suggesting that AERRIE is marginally regulating mesenchymal markers and transcription factors. This study identifies AERRIE as a novel factor in EndMT, but its mechanism of action still needs to be elucidated. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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12 pages, 1724 KiB  
Article
P62 Links the Autophagy Pathway and the Ubiquitin–Proteasome System in Endothelial Cells during Atherosclerosis
by SeJeong Kim, WoongJin Lee and KyoungJoo Cho
Int. J. Mol. Sci. 2021, 22(15), 7791; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157791 - 21 Jul 2021
Cited by 8 | Viewed by 3284
Abstract
Among autophagy-related molecules, p62/SQSTM1 is an adaptor for identifying and delivering intracellular cargo for degradation. Since ubiquitination is reversible, it has a switch role in autophagy. Ubiquitination is also involved in regulating autophagy in a timely manner. This study aimed to elucidate how [...] Read more.
Among autophagy-related molecules, p62/SQSTM1 is an adaptor for identifying and delivering intracellular cargo for degradation. Since ubiquitination is reversible, it has a switch role in autophagy. Ubiquitination is also involved in regulating autophagy in a timely manner. This study aimed to elucidate how p62-mediated autophagy is regulated in human endothelial cells and macrophages under atherosclerotic conditions, focusing on the lysosomal and proteasomal pathways. Co-cultured HUVECs and THP-1 cells were exposed to oxLDL (50 μg/mL) and autophagy was assessed. To downregulate p62, siRNA was administered, and the E3 ligases were inhibited by Heclin or MLN4924 treatment under the condition that cellular inflammatory processes were stimulated by oxLDL simultaneously initiated autophagy. Downregulating p62 induced an alternative degradation system, and the E3 ligases were found to be involved in the progression of atherosclerosis. Collectively, the present study demonstrated that the endothelial lipid accumulation under atherosclerotic conditions was caused by lysosomal dysfunction associated with autophagy. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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10 pages, 1217 KiB  
Article
Cell Biological Responses after Shiga Toxin-1 Exposure to Primary Human Glomerular Microvascular Endothelial Cells from Pediatric and Adult Origin
by Wouter J. C. Feitz, Petra A. van Setten, Thea J. A. M. van der Velden, Christoph Licht, Lambert P. J. W. van den Heuvel and Nicole C. A. J. van de Kar
Int. J. Mol. Sci. 2021, 22(11), 5615; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115615 - 25 May 2021
Cited by 2 | Viewed by 2075
Abstract
Hemolytic uremic syndrome (HUS) is characterized by a triad of symptoms consisting of hemolytic anemia, thrombocytopenia and acute renal failure. The most common form of HUS is caused by an infection with Shiga toxin (Stx) producing Escherichia coli bacteria (STEC-HUS), and the kidneys [...] Read more.
Hemolytic uremic syndrome (HUS) is characterized by a triad of symptoms consisting of hemolytic anemia, thrombocytopenia and acute renal failure. The most common form of HUS is caused by an infection with Shiga toxin (Stx) producing Escherichia coli bacteria (STEC-HUS), and the kidneys are the major organs affected. The development of HUS after an infection with Stx occurs most frequently in children under the age of 5 years. However, the cause for the higher incidence of STEC-HUS in children compared to adults is still not well understood. Human glomerular microvascular endothelial cells (HGMVECs) isolated and cultured from pediatric and adult kidney tissue were investigated with respect to Stx binding and different cellular responses. Shiga toxin-1 (Stx-1) inhibited protein synthesis in both pediatric and adult HGMVECs in a dose-dependent manner at basal conditions. The preincubation of pediatric and adult HGMVECs for 24 hrs with TNFα resulted in increased Stx binding to the cell surface and a 20–40% increase in protein synthesis inhibition in both age groups. A decreased proliferation of cells was found when a bromodeoxyuridine (BrdU) assay was performed. A trend towards a delay in endothelial wound closure was visible when pediatric and adult HGMVECs were incubated with Stx-1. Although minor differences between pediatric HGMVECs and adult HGMVECs were found in the assays applied in this study, no significant differences were observed. In conclusion, we have demonstrated that in vitro primary HGMVECs isolated from pediatric and adult kidneys do not significantly differ in their cell biological responses to Stx-1. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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19 pages, 3683 KiB  
Article
Efficacy of the Piperidine Nitroxide 4-MethoxyTEMPO in Ameliorating Serum Amyloid A-Mediated Vascular Inflammation
by Nathan J. Martin, Belal Chami, Abigail Vallejo, Albaraa A. Mojadadi, Paul K. Witting and Gulfam Ahmad
Int. J. Mol. Sci. 2021, 22(9), 4549; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094549 - 27 Apr 2021
Cited by 4 | Viewed by 2310
Abstract
Intracellular redox imbalance in endothelial cells (EC) can lead to endothelial dysfunction, which underpins cardiovascular diseases (CVD). The acute phase serum amyloid A (SAA) elicits inflammation through stimulating production of reactive oxygen species (ROS). The cyclic nitroxide 4-MethoxyTEMPO (4-MetT) is a superoxide dismutase [...] Read more.
Intracellular redox imbalance in endothelial cells (EC) can lead to endothelial dysfunction, which underpins cardiovascular diseases (CVD). The acute phase serum amyloid A (SAA) elicits inflammation through stimulating production of reactive oxygen species (ROS). The cyclic nitroxide 4-MethoxyTEMPO (4-MetT) is a superoxide dismutase mimetic that suppresses oxidant formation and inflammation. The aim of this study was to investigate whether 4-MetT inhibits SAA-mediated activation of cultured primary human aortic EC (HAEC). Co-incubating cells with 4-MetT inhibited SAA-mediated increases in adhesion molecules (VCAM-1, ICAM-1, E-selectin, and JAM-C). Pre-treatment of cells with 4-MetT mitigated SAA-mediated increases in transcriptionally activated NF-κB-p65 and P120 Catenin (a stabilizer of Cadherin expression). Mitochondrial respiration and ROS generation (mtROS) were adversely affected by SAA with decreased respiratory reserve capacity, elevated maximal respiration and proton leakage all characteristic of SAA-treated HAEC. This altered respiration manifested as a loss of mitochondrial membrane potential (confirmed by a decrease in TMRM fluorescence), and increased mtROS production as assessed with MitoSox Red. These SAA-linked impacts on mitochondria were mitigated by 4-MetT resulting in restoration of HAEC nitric oxide bioavailability as confirmed by assessing cyclic guanosine monophosphate (cGMP) levels. Thus, 4-MetT ameliorates SAA-mediated endothelial dysfunction through normalising EC redox homeostasis. Subject to further validation in in vivo settings; these outcomes suggest its potential as a therapeutic in the setting of cardiovascular pathologies where elevated SAA and endothelial dysfunction is linked to enhanced CVD. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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16 pages, 2678 KiB  
Article
Activation of the Complement System on Human Endothelial Cells by Urban Particulate Matter Triggers Inflammation-Related Protein Production
by Myoung Su Choi, Hyungtaek Jeon, Seung-Min Yoo and Myung-Shin Lee
Int. J. Mol. Sci. 2021, 22(7), 3336; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073336 - 24 Mar 2021
Cited by 6 | Viewed by 2712
Abstract
Exposure to particulate matter (PM) is becoming a major global health issue. The amount and time of exposure to PM are known to be closely associated with cardiovascular diseases. However, the mechanism through which PM affects the vascular system is still not clear. [...] Read more.
Exposure to particulate matter (PM) is becoming a major global health issue. The amount and time of exposure to PM are known to be closely associated with cardiovascular diseases. However, the mechanism through which PM affects the vascular system is still not clear. Endothelial cells line the interior surface of blood vessels and actively interact with plasma proteins, including the complement system. Unregulated complement activation caused by invaders, such as pollutants, may promote endothelial inflammation. In the present study, we sought to investigate whether urban PM (UPM) acts on the endothelial environment via the complement system. UPM-treated human endothelial cells with normal human serum showed the deposition of membrane attack complexes (MACs) on the cell surface via the alternative pathway of the complement system. Despite the formation of MACs, cell death was not observed, and cell proliferation was increased in UPM-mediated complement activation. Furthermore, complement activation on endothelial cells stimulated the production of inflammation-related proteins. Our results revealed that UPM could activate the complement system in human endothelial cells and that complement activation regulated inflammatory reaction in microenvironment. These findings provide clues with regard to the role of the complement system in pathophysiologic events of vascular disease elicited by air pollution. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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13 pages, 12187 KiB  
Article
Chloroquine-Induced Accumulation of Autophagosomes and Lipids in the Endothelium
by Ewelina Bik, Lukasz Mateuszuk, Jagoda Orleanska, Malgorzata Baranska, Stefan Chlopicki and Katarzyna Majzner
Int. J. Mol. Sci. 2021, 22(5), 2401; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052401 - 27 Feb 2021
Cited by 15 | Viewed by 5751
Abstract
Chloroquine (CQ) is an antimalarial drug known to inhibit autophagy flux by impairing autophagosome–lysosome fusion. We hypothesized that autophagy flux altered by CQ has a considerable influence on the lipid composition of endothelial cells. Thus, we investigated endothelial responses induced by CQ on [...] Read more.
Chloroquine (CQ) is an antimalarial drug known to inhibit autophagy flux by impairing autophagosome–lysosome fusion. We hypothesized that autophagy flux altered by CQ has a considerable influence on the lipid composition of endothelial cells. Thus, we investigated endothelial responses induced by CQ on human microvascular endothelial cells (HMEC-1). HMEC-1 cells after CQ exposure were measured using a combined methodology based on label-free Raman and fluorescence imaging. Raman spectroscopy was applied to characterize subtle chemical changes in lipid contents and their distribution in the cells, while the fluorescence staining (LipidTox, LysoTracker and LC3) was used as a reference method. The results showed that CQ was not toxic to endothelial cells and did not result in the endothelial inflammation at concentrations of 1–30 µM. Notwithstanding, it yielded an increased intensity of LipidTox, LysoTracker, and LC3 staining, suggesting changes in the content of neutral lipids, lysosomotropism, and autophagy inhibition, respectively. The CQ-induced endothelial response was associated with lipid accumulation and was characterized by Raman spectroscopy. CQ-induced autophagosome accumulation in the endothelium is featured by a pronounced alteration in the lipid profile, but not in the endothelial inflammation. Raman-based assessment of CQ-induced biochemical changes offers a better understanding of the autophagy mechanism in the endothelial cells. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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15 pages, 11231 KiB  
Article
Potential Effects of Nonadherent on Adherent Human Umbilical Venous Endothelial Cells in Cell Culture
by Christian Schulz, Anne Krüger-Genge, Andreas Lendlein, Jan-Heiner Küpper and Friedrich Jung
Int. J. Mol. Sci. 2021, 22(3), 1493; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031493 - 02 Feb 2021
Cited by 2 | Viewed by 3718
Abstract
The adherence and shear-resistance of human umbilical venous endothelial cells (HUVEC) on polymers is determined in vitro in order to qualify cardiovascular implant materials. In these tests, variable fractions of HUVEC do not adhere to the material but remain suspended in the culture [...] Read more.
The adherence and shear-resistance of human umbilical venous endothelial cells (HUVEC) on polymers is determined in vitro in order to qualify cardiovascular implant materials. In these tests, variable fractions of HUVEC do not adhere to the material but remain suspended in the culture medium. Nonadherent HUVEC usually stop growing, rapidly lose their viability and can release mediators able to influence the growth and function of the adherent HUVEC. The aim of this study was the investigation of the time dependent behaviour of HUVEC under controlled nonadherent conditions, in order to gain insights into potential influences of these cells on their surrounding environment in particular adherent HUVEC in the context of in vitro biofunctionality assessment of cardiovascular implant materials. Data from adherent or nonadherent HUVEC growing on polystyrene-based cell adhesive tissue culture plates (TCP) or nonadhesive low attachment plates (LAP) allow to calculate the number of mediators released into the culture medium either from adherent or nonadherent cells. Thus, the source of the inflammatory mediators can be identified. For nonadherent HUVEC, a time-dependent aggregation without further proliferation was observed. The rate of apoptotic/dead HUVEC progressively increased over 90% within two days. Concomitant with distinct blebbing and loss of membrane integrity over time, augmented releases of prostacyclin (PGI2, up to 2.91 ± 0.62 fg/cell) and platelet-derived growth factor BB (PDGF-BB, up to 1.46 ± 0.42 fg/cell) were detected. The study revealed that nonadherent, dying HUVEC released mediators, which can influence the surrounding microenvironment and thereby the results of in vitro biofunctionality assessment of cardiovascular implant materials. Neglecting nonadherent HUVEC bears the risk for under- or overestimation of the materials endothelialization potential, which could lead to the loss of relevant candidates or to uncertainty with regard to their suitability for cardiac applications. One approach to minimize the influence from nonadherent endothelial cells could be their removal shortly after observing initial cell adhesion. However, this would require an individual adaptation of the study design, depending on the properties of the biomaterial used. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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19 pages, 2453 KiB  
Article
Hyperglycemic Condition Causes Pro-Inflammatory and Permeability Alterations Associated with Monocyte Recruitment and Deregulated NFκB/PPARγ Pathways on Cerebral Endothelial Cells: Evidence for Polyphenols Uptake and Protective Effect
by Janice Taïlé, Jessica Patché, Bryan Veeren and Marie-Paule Gonthier
Int. J. Mol. Sci. 2021, 22(3), 1385; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031385 - 30 Jan 2021
Cited by 22 | Viewed by 2879
Abstract
Hyperglycemia alters the function of cerebral endothelial cells from the blood-brain barrier, increasing the risk of cerebrovascular complications during diabetes. This study evaluated the protective effect of polyphenols on inflammatory and permeability markers on bEnd3 cerebral endothelial cells exposed to high glucose concentration. [...] Read more.
Hyperglycemia alters the function of cerebral endothelial cells from the blood-brain barrier, increasing the risk of cerebrovascular complications during diabetes. This study evaluated the protective effect of polyphenols on inflammatory and permeability markers on bEnd3 cerebral endothelial cells exposed to high glucose concentration. Results show that hyperglycemic condition increased nuclear factor kappa B (NFκB) activity, deregulated the expression of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10) and endothelial-leukocyte adhesion molecule (E-selectin) genes, raised MCP-1 secretion and elevated monocyte adhesion and transendothelial migration. High glucose decreased occludin, claudin-5, zona occludens-1 (ZO-1) and zona occludens-2 (ZO-2) tight junctions production and altered the endothelial permeability. Characterized polyphenolic extracts from the French medicinal plants Antirhea borbonica, Ayapana triplinervis, Dodonaea viscosa and Terminalia bentzoe, and their major polyphenols quercetin, caffeic, chlorogenic and gallic acids limited the pro-inflammatory and permeability alterations caused by high glucose. Peroxisome proliferator-activated receptor gamma (PPARγ) agonist also attenuated these damages while PPARγ antagonist aggravated them, suggesting PPARγ protective action. Interestingly, polyphenols improved PPARγ gene expression lowered by high glucose. Moreover, polyphenols were detected at the intracellular level or membrane-bound to cells, with evidence for breast cancer resistance protein (BCRP) efflux transporter role. Altogether, these findings emphasize the ability of polyphenols to protect cerebral endothelial cells in hyperglycemic condition and their relevance for pharmacological strategies aiming to limit cerebrovascular disorders in diabetes. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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15 pages, 5634 KiB  
Article
Lipid Raft Association Stabilizes VEGF Receptor 2 in Endothelial Cells
by Ibukunoluwapo O. Zabroski and Matthew A. Nugent
Int. J. Mol. Sci. 2021, 22(2), 798; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020798 - 14 Jan 2021
Cited by 22 | Viewed by 2729
Abstract
The binding of vascular endothelial growth factor A (VEGF) to VEGF receptor-2 (VEGFR-2) stimulates angiogenic signaling. Lipid rafts are cholesterol-dense regions of the plasma membrane that serve as an organizational platform for biomolecules. Although VEGFR2 has been shown to colocalize with lipid rafts [...] Read more.
The binding of vascular endothelial growth factor A (VEGF) to VEGF receptor-2 (VEGFR-2) stimulates angiogenic signaling. Lipid rafts are cholesterol-dense regions of the plasma membrane that serve as an organizational platform for biomolecules. Although VEGFR2 has been shown to colocalize with lipid rafts to regulate its activation, the effect of lipid rafts on non-activated VEGFR2 has not been explored. Here, we characterized the involvement of lipid rafts in modulating the stability of non-activated VEGFR2 in endothelial cells using raft disrupting agents: methyl-β-cyclodextrin, sphingomyelinase and simvastatin. Disrupting lipid rafts selectively decreased the levels of non-activated VEGFR2 as a result of increased lysosomal degradation. The decreased expression of VEGFR2 translated to reduced VEGF-activation of the extracellular signal-regulated protein kinases (ERK). Overall, our results indicate that lipid rafts stabilize VEGFR2 and its associated signal transduction activities required for angiogenesis. Thus, modulation of lipid rafts may provide a means to regulate the sensitivity of endothelial cells to VEGF stimulation. Indeed, the ability of simvastatin to down regulate VEGFR2 and inhibit VEGF activity suggest a potential mechanism underlying the observation that this drug improves outcomes in the treatment of certain cancers. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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Review

Jump to: Editorial, Research

13 pages, 1292 KiB  
Review
The RhoGEF Trio: A Protein with a Wide Range of Functions in the Vascular Endothelium
by Lanette Kempers, Amber J. M. Driessen, Jos van Rijssel, Martijn A. Nolte and Jaap D. van Buul
Int. J. Mol. Sci. 2021, 22(18), 10168; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810168 - 21 Sep 2021
Cited by 7 | Viewed by 3172
Abstract
Many cellular processes are controlled by small GTPases, which can be activated by guanine nucleotide exchange factors (GEFs). The RhoGEF Trio contains two GEF domains that differentially activate the small GTPases such as Rac1/RhoG and RhoA. These small RhoGTPases are mainly involved in [...] Read more.
Many cellular processes are controlled by small GTPases, which can be activated by guanine nucleotide exchange factors (GEFs). The RhoGEF Trio contains two GEF domains that differentially activate the small GTPases such as Rac1/RhoG and RhoA. These small RhoGTPases are mainly involved in the remodeling of the actin cytoskeleton. In the endothelium, they regulate junctional stabilization and play a crucial role in angiogenesis and endothelial barrier integrity. Multiple extracellular signals originating from different vascular processes can influence the activity of Trio and thereby the regulation of the forementioned small GTPases and actin cytoskeleton. This review elucidates how various signals regulate Trio in a distinct manner, resulting in different functional outcomes that are crucial for endothelial cell function in response to inflammation. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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24 pages, 2371 KiB  
Review
Properties and Application of Cell-Free DNA as a Clinical Biomarker
by Felipe Silva de Miranda, Valério Garrone Barauna, Leandro dos Santos, Gustavo Costa, Paula Frizera Vassallo and Luciene Cristina Gastalho Campos
Int. J. Mol. Sci. 2021, 22(17), 9110; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179110 - 24 Aug 2021
Cited by 26 | Viewed by 6097
Abstract
Biomarkers are valuable tools in clinical practice. In 2001, the National Institutes of Health (NIH) standardized the definition of a biomarker as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to [...] Read more.
Biomarkers are valuable tools in clinical practice. In 2001, the National Institutes of Health (NIH) standardized the definition of a biomarker as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. A biomarker has clinical relevance when it presents precision, standardization and reproducibility, suitability to the patient, straightforward interpretation by clinicians, and high sensitivity and/or specificity by the parameter it proposes to identify. Thus, serum biomarkers should have advantages related to the simplicity of the procedures and to the fact that venous blood collection is commonplace in clinical practice. We described the potentiality of cfDNA as a general clinical biomarker and focused on endothelial dysfunction. Circulating cell-free DNA (cfDNA) refers to extracellular DNA present in body fluid that may be derived from both normal and diseased cells. An increasing number of studies demonstrate the potential use of cfDNA as a noninvasive biomarker to determine physiologic and pathologic conditions. However, although still scarce, increasing evidence has been reported regarding using cfDNA in cardiovascular diseases. Here, we have reviewed the history of cfDNA, its source, molecular features, and release mechanism. We also show recent studies that have investigated cfDNA as a possible marker of endothelial damage in clinical settings. In the cardiovascular system, the studies are quite new, and although interesting, stronger evidence is still needed. However, some drawbacks in cfDNA methodologies should be overcome before its recommendation as a biomarker in the clinical setting. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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23 pages, 2224 KiB  
Review
Secretome and Tunneling Nanotubes: A Multilevel Network for Long Range Intercellular Communication between Endothelial Cells and Distant Cells
by Béatrice Charreau
Int. J. Mol. Sci. 2021, 22(15), 7971; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157971 - 26 Jul 2021
Cited by 7 | Viewed by 3310
Abstract
As a cellular interface between the blood and tissues, the endothelial cell (EC) monolayer is involved in the control of key functions including vascular tone, permeability and homeostasis, leucocyte trafficking and hemostasis. EC regulatory functions require long-distance communications between ECs, circulating hematopoietic cells [...] Read more.
As a cellular interface between the blood and tissues, the endothelial cell (EC) monolayer is involved in the control of key functions including vascular tone, permeability and homeostasis, leucocyte trafficking and hemostasis. EC regulatory functions require long-distance communications between ECs, circulating hematopoietic cells and other vascular cells for efficient adjusting thrombosis, angiogenesis, inflammation, infection and immunity. This intercellular crosstalk operates through the extracellular space and is orchestrated in part by the secretory pathway and the exocytosis of Weibel Palade Bodies (WPBs), secretory granules and extracellular vesicles (EVs). WPBs and secretory granules allow both immediate release and regulated exocytosis of messengers such as cytokines, chemokines, extracellular membrane proteins, coagulation or growth factors. The ectodomain shedding of transmembrane protein further provide the release of both receptor and ligands with key regulatory activities on target cells. Thin tubular membranous channels termed tunneling nanotubes (TNTs) may also connect EC with distant cells. EVs, in particular exosomes, and TNTs may contain and transfer different biomolecules (e.g., signaling mediators, proteins, lipids, and microRNAs) or pathogens and have emerged as a major triggers of horizontal intercellular transfer of information. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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10 pages, 3211 KiB  
Review
The Cytoplasmic Actins in the Regulation of Endothelial Cell Function
by Vera B. Dugina, Galina S. Shagieva, Anton S. Shakhov and Irina B. Alieva
Int. J. Mol. Sci. 2021, 22(15), 7836; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157836 - 22 Jul 2021
Cited by 22 | Viewed by 2605
Abstract
The primary function of the endothelial cells (EC) lining the inner surface of all vessels is to regulate permeability of vascular walls and to control exchange between circulating blood and tissue fluids of organs. The EC actin cytoskeleton plays a crucial role in [...] Read more.
The primary function of the endothelial cells (EC) lining the inner surface of all vessels is to regulate permeability of vascular walls and to control exchange between circulating blood and tissue fluids of organs. The EC actin cytoskeleton plays a crucial role in maintaining endothelial barrier function. Actin cytoskeleton reorganization result in EC contraction and provides a structural basis for the increase in vascular permeability, which is typical for many diseases. Actin cytoskeleton in non-muscle cells presented two actin isoforms: non-muscle β-cytoplasmic and γ-cytoplasmic actins (β-actins and γ-actins), which are encoded by ACTB and ACTG1 genes, respectively. They are ubiquitously expressed in the different cells in vivo and in vitro and the β/γ-actin ratio depends on the cell type. Both cytoplasmic actins are essential for cell survival, but they perform various functions in the interphase and cell division and play different roles in neoplastic transformation. In this review, we briefly summarize the research results of recent years and consider the features of the cytoplasmic actins: The spatial organization in close connection with their functional activity in different cell types by focusing on endothelial cells. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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21 pages, 3274 KiB  
Review
Emerging Approaches to Understanding Microvascular Endothelial Heterogeneity: A Roadmap for Developing Anti-Inflammatory Therapeutics
by Qingliang Yang, Harshani Wijerathne, Jordan C. Langston, Mohammad F. Kiani and Laurie E. Kilpatrick
Int. J. Mol. Sci. 2021, 22(15), 7770; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157770 - 21 Jul 2021
Cited by 20 | Viewed by 4316
Abstract
The endothelium is the inner layer of all blood vessels and it regulates hemostasis. It also plays an active role in the regulation of the systemic inflammatory response. Systemic inflammatory disease often results in alterations in vascular endothelium barrier function, increased permeability, excessive [...] Read more.
The endothelium is the inner layer of all blood vessels and it regulates hemostasis. It also plays an active role in the regulation of the systemic inflammatory response. Systemic inflammatory disease often results in alterations in vascular endothelium barrier function, increased permeability, excessive leukocyte trafficking, and reactive oxygen species production, leading to organ damage. Therapeutics targeting endothelium inflammation are urgently needed, but strong concerns regarding the level of phenotypic heterogeneity of microvascular endothelial cells between different organs and species have been expressed. Microvascular endothelial cell heterogeneity in different organs and organ-specific variations in endothelial cell structure and function are regulated by intrinsic signals that are differentially expressed across organs and species; a result of this is that neutrophil recruitment to discrete organs may be regulated differently. In this review, we will discuss the morphological and functional variations in differently originated microvascular endothelia and discuss how these variances affect systemic function in response to inflammation. We will review emerging in vivo and in vitro models and techniques, including microphysiological devices, proteomics, and RNA sequencing used to study the cellular and molecular heterogeneity of endothelia from different organs. A better understanding of microvascular endothelial cell heterogeneity will provide a roadmap for developing novel therapeutics to target the endothelium. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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22 pages, 1055 KiB  
Review
Molecular Characteristics of RAGE and Advances in Small-Molecule Inhibitors
by Hyeon Jin Kim, Mi Suk Jeong and Se Bok Jang
Int. J. Mol. Sci. 2021, 22(13), 6904; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136904 - 27 Jun 2021
Cited by 42 | Viewed by 5029
Abstract
Receptor for advanced glycation end-products (RAGE) is a member of the immunoglobulin superfamily. RAGE binds and mediates cellular responses to a range of DAMPs (damage-associated molecular pattern molecules), such as AGEs, HMGB1, and S100/calgranulins, and as an innate immune sensor, can recognize microbial [...] Read more.
Receptor for advanced glycation end-products (RAGE) is a member of the immunoglobulin superfamily. RAGE binds and mediates cellular responses to a range of DAMPs (damage-associated molecular pattern molecules), such as AGEs, HMGB1, and S100/calgranulins, and as an innate immune sensor, can recognize microbial PAMPs (pathogen-associated molecular pattern molecules), including bacterial LPS, bacterial DNA, and viral and parasitic proteins. RAGE and its ligands stimulate the activations of diverse pathways, such as p38MAPK, ERK1/2, Cdc42/Rac, and JNK, and trigger cascades of diverse signaling events that are involved in a wide spectrum of diseases, including diabetes mellitus, inflammatory, vascular and neurodegenerative diseases, atherothrombosis, and cancer. Thus, the targeted inhibition of RAGE or its ligands is considered an important strategy for the treatment of cancer and chronic inflammatory diseases. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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19 pages, 3153 KiB  
Review
Tumor Vessels Fuel the Fire in Glioblastoma
by Sara Rosińska and Julie Gavard
Int. J. Mol. Sci. 2021, 22(12), 6514; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126514 - 17 Jun 2021
Cited by 33 | Viewed by 4583
Abstract
Glioblastoma, a subset of aggressive brain tumors, deploy several means to increase blood vessel supply dedicated to the tumor mass. This includes typical program borrowed from embryonic development, such as vasculogenesis and sprouting angiogenesis, as well as unconventional processes, including co-option, vascular mimicry, [...] Read more.
Glioblastoma, a subset of aggressive brain tumors, deploy several means to increase blood vessel supply dedicated to the tumor mass. This includes typical program borrowed from embryonic development, such as vasculogenesis and sprouting angiogenesis, as well as unconventional processes, including co-option, vascular mimicry, and transdifferentiation, in which tumor cells are pro-actively engaged. However, these neo-generated vascular networks are morphologically and functionally abnormal, suggesting that the vascularization processes are rather inefficient in the tumor ecosystem. In this review, we reiterate the specificities of each neovascularization modality in glioblastoma, and, how they can be hampered mechanistically in the perspective of anti-cancer therapies. Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology)
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