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Vascular Signalling
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Vascular Signalling

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 87436

Special Issue Editors

Prof. Patric Turowski

E-Mail Website
Guest Editor
UCL Institute of Ophthalmology, University College of London, London EC1V 9EL, UK
Interests: endothelial cells; blood–neural barrier; vascular permeability; cell signalling; protein phosphorylation
Dr. Silvia Dragoni

E-Mail Website
Guest Editor
UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK
Interests: vascular endothelial growth factor; calcium signalling; vascular leakage; retina

Special Issue Information

Dear Colleagues,

In all vertebrates, the closed blood and open lymph circulatory systems are essential for the delivery of nutrients and oxygen to tissues, waste clearance, and immune function. Endothelial cells line the vessel walls and regulate the passage of molecules and cells to and from the underlying tissue. Mural cells, such as vascular smooth muscle cells and pericytes, define the nature of the vasculature, which displays vast differences: physically, such as seen between arteries and veins, as well as functionally and morphologically, as illustrated by filtrating microvessels in the kidney and the highly impermeable blood–brain barrier.

The vasculature is highly dynamic, with complex cellular programmes regulating new blood vessel formation through vasculogenesis or angiogenesis, lumen formation, and endothelial cell migration in mature vessels. Recent data also demonstrate the intimate integration of dynamic vascular functions and metabolic demands and availability.

Importantly, with regard to human disease, vascular abnormalities underly or accompany the majority of cardiovascular diseases, such as arteriosclerosis, but also a wide variety of a priori non-vascular diseases, such as cancer, inflammation, neurodegeneration, or metabolic diseases.

Central to the homeostatic and pathological mechanisms of the vasculature are highly specific intracellular and intercellular signalling, as well as genetic programmes, which are exquisitely responsive to growth factors, cytokines, nucleic acids, and lipids.

The aim of this Special Issue is to assemble original data and reviews illustrating the plethora of cellular signalling that typifies vascular behavior and responsiveness during health and disease. We hope that contributions from expert laboratories will result in a compendium supporting researchers with a vested interest in vascular function, and those aiming to be intitiated into this fascinating area of vertebrate biology.

Prof. Patric Turowski
Dr. Silvia Dragoni
Guest Editors

Manuscript Submission Information

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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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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
  • cell signalling
  • vasculogenesis
  • angiogenesis
  • cardiovascular diseases
  • inflammation
  • pericytes
  • vascular smooth muscle cells

Published Papers (21 papers)

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Editorial

Jump to: Research, Review

6 pages, 231 KiB  
Editorial
Vascular Signalling
by Silvia Dragoni and Patric Turowski
Cells 2023, 12(16), 2038; https://doi.org/10.3390/cells12162038 - 10 Aug 2023
Viewed by 610
Abstract
In all vertebrates, closed blood and open lymph circulatory systems are essential for the delivery of nutrients and oxygen to tissues, waste clearance, and immune function [...] Full article
(This article belongs to the Special Issue Vascular Signalling)

Research

Jump to: Editorial, Review

17 pages, 3309 KiB  
Article
The Role of Heparan Sulfate and Neuropilin 2 in VEGFA Signaling in Human Endothelial Tip Cells and Non-Tip Cells during Angiogenesis In Vitro
by Marchien G. Dallinga, Yasmin I. Habani, Alinda W. M. Schimmel, Geesje M. Dallinga-Thie, Cornelis J. F. van Noorden, Ingeborg Klaassen and Reinier O. Schlingemann
Cells 2021, 10(4), 926; https://doi.org/10.3390/cells10040926 - 16 Apr 2021
Cited by 11 | Viewed by 2683
Abstract
During angiogenesis, vascular endothelial growth factor A (VEGFA) regulates endothelial cell (EC) survival, tip cell formation, and stalk cell proliferation via VEGF receptor 2 (VEGFR2). VEGFR2 can interact with VEGFR2 co-receptors such as heparan sulfate proteoglycans (HSPGs) and neuropilin 2 (NRP2), but the [...] Read more.
During angiogenesis, vascular endothelial growth factor A (VEGFA) regulates endothelial cell (EC) survival, tip cell formation, and stalk cell proliferation via VEGF receptor 2 (VEGFR2). VEGFR2 can interact with VEGFR2 co-receptors such as heparan sulfate proteoglycans (HSPGs) and neuropilin 2 (NRP2), but the exact roles of these co-receptors, or of sulfatase 2 (SULF2), an enzyme that removes sulfate groups from HSPGs and inhibits HSPG-mediated uptake of very low density lipoprotein (VLDL), in angiogenesis and tip cell biology are unknown. In the present study, we investigated whether the modulation of binding of VEGFA to VEGFR2 by knockdown of SULF2 or NRP2 affects sprouting angiogenesis, tip cell formation, proliferation of non-tip cells, and EC survival, or uptake of VLDL. To this end, we employed VEGFA splice variant 121, which lacks an HSPG binding domain, and VEGFA splice variant 165, which does have this domain, in in vitro models of angiogenic tip cells and vascular sprouting. We conclude that VEGFA165 and VEGFA121 have similar inducing effects on tip cells and sprouting in vitro, and that the binding of VEGFA165 to HSPGs in the extracellular matrix does not seem to play a role, as knockdown of SULF2 did not alter these effects. Co-binding of NRP2 appears to regulate VEGFA–VEGFR2-induced sprout initiation, but not tip cell formation. Finally, as the addition of VLDL increased sprout formation but not tip cell formation, and as VLDL uptake was limited to non-tip cells, our findings suggest that VLDL plays a role in sprout formation by providing biomass for stalk cell proliferation. Full article
(This article belongs to the Special Issue Vascular Signalling)
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14 pages, 1851 KiB  
Article
ADAM10-Mediated Cleavage of ICAM-1 Is Involved in Neutrophil Transendothelial Migration
by Sofia K. H. Morsing, Timo Rademakers, Sanne L. N. Brouns, Anne-Marieke D. van Stalborch, Marjo M. P. C. Donners and Jaap D. van Buul
Cells 2021, 10(2), 232; https://doi.org/10.3390/cells10020232 - 25 Jan 2021
Cited by 15 | Viewed by 2841
Abstract
To efficiently cross the endothelial barrier during inflammation, neutrophils first firmly adhere to the endothelial surface using the endothelial adhesion molecule ICAM-1. Upon actual transmigration, the release from ICAM-1 is required. While Integrin LFA1/Mac1 de-activation is one described mechanism that leads to this, [...] Read more.
To efficiently cross the endothelial barrier during inflammation, neutrophils first firmly adhere to the endothelial surface using the endothelial adhesion molecule ICAM-1. Upon actual transmigration, the release from ICAM-1 is required. While Integrin LFA1/Mac1 de-activation is one described mechanism that leads to this, direct cleavage of ICAM-1 from the endothelium represents a second option. We found that a disintegrin and metalloprotease 10 (ADAM10) cleaves the extracellular domain of ICAM-1 from the endothelial surface. Silencing or inhibiting endothelial ADAM10 impaired the efficiency of neutrophils to cross the endothelium, suggesting that neutrophils use endothelial ADAM10 to dissociate from ICAM-1. Indeed, when measuring transmigration kinetics, neutrophils took almost twice as much time to finish the diapedesis step when ADAM10 was silenced. Importantly, we found increased levels of ICAM-1 on the transmigrating neutrophils when crossing an endothelial monolayer where such increased levels were not detected when neutrophils crossed bare filters. Using ICAM-1-GFP-expressing endothelial cells, we show that ICAM-1 presence on the neutrophils can also occur by membrane transfer from the endothelium to the neutrophil. Based on these findings, we conclude that endothelial ADAM10 contributes in part to neutrophil transendothelial migration by cleaving ICAM-1, thereby supporting the release of neutrophils from the endothelium during the final diapedesis step. Full article
(This article belongs to the Special Issue Vascular Signalling)
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18 pages, 2564 KiB  
Article
Endothelial Protease Activated Receptor 1 (PAR1) Signalling Is Required for Lymphocyte Transmigration across Brain Microvascular Endothelial Cells
by Silvia Dragoni, Anna Papageorgiou, Caroline Araiz, John Greenwood and Patric Turowski
Cells 2020, 9(12), 2723; https://doi.org/10.3390/cells9122723 - 21 Dec 2020
Cited by 6 | Viewed by 2871
Abstract
Lymphocyte transendothelial migration (TEM) relies on ICAM-1 engagement on the luminal surface of the endothelial cells (ECs). In blood–brain barrier (BBB) ECs, ICAM-1 triggers TEM signalling, including through JNK MAP kinase and AMP-activated protein kinase (AMPK), which lead to the phosphorylation and internalisation [...] Read more.
Lymphocyte transendothelial migration (TEM) relies on ICAM-1 engagement on the luminal surface of the endothelial cells (ECs). In blood–brain barrier (BBB) ECs, ICAM-1 triggers TEM signalling, including through JNK MAP kinase and AMP-activated protein kinase (AMPK), which lead to the phosphorylation and internalisation of the adherens junction protein VE-cadherin. In addition to ICAM-1, G protein-coupled receptors (GPCRs) are also required for lymphocytes TEM across BBB ECs. Here, we investigated the role of protease activated GPCRs (PARs) and found a specific role for PAR1 in support of lymphocyte TEM across BBB ECs in vitro. PAR1 requirement for TEM was confirmed using protease inhibitors, specific small molecule and peptide antagonists, function blocking antibodies and siRNA-mediated knockdown. In BBB ECs, PAR1 stimulation led to activation of signalling pathways essential to TEM; notably involving JNK and endothelial nitric oxide synthase (eNOS), with the latter downstream of AMPK. In turn, nitric oxide production through eNOS was essential for TEM by modulating VE-cadherin on Y731. Collectively, our data showed that non-canonical PAR1 activation by a lymphocyte-released serine protease is required for lymphocyte TEM across the BBB in vitro, and that this feeds into previously established ICAM-1-mediated endothelial TEM signalling pathways. Full article
(This article belongs to the Special Issue Vascular Signalling)
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22 pages, 14975 KiB  
Article
Amyloid-β Precursor Protein APP Down-Regulation Alters Actin Cytoskeleton-Interacting Proteins in Endothelial Cells
by Emma Ristori, Vittoria Cicaloni, Laura Salvini, Laura Tinti, Cristina Tinti, Michael Simons, Federico Corti, Sandra Donnini and Marina Ziche
Cells 2020, 9(11), 2506; https://doi.org/10.3390/cells9112506 - 19 Nov 2020
Cited by 11 | Viewed by 3645
Abstract
The amyloid-β precursor protein (APP) is a ubiquitous membrane protein often associated with Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Despite its role in the development of the pathogenesis, APP exerts several physiological roles that have been mainly investigated in neuronal tissue. [...] Read more.
The amyloid-β precursor protein (APP) is a ubiquitous membrane protein often associated with Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Despite its role in the development of the pathogenesis, APP exerts several physiological roles that have been mainly investigated in neuronal tissue. To date, the role of APP in vasculature and endothelial cells has not been fully elucidated. In this study, we used molecular and proteomic approaches to identify and investigate major cellular targets of APP down-regulation in endothelial cells. We found that APP is necessary for endothelial cells proliferation, migration and adhesion. The loss of APP alters focal adhesion stability and cell–cell junctions’ expression. Moreover, APP is necessary to mediate endothelial response to the VEGF-A growth factor. Finally, we document that APP propagates exogenous stimuli and mediates cellular response in endothelial cells by modulating the Scr/FAK signaling pathway. Thus, the intact expression and processing of APP is required for normal endothelial function. The identification of molecular mechanisms responsible for vasoprotective properties of endothelial APP may have an impact on clinical efforts to preserve and protect healthy vasculature in patients at risk of the development of cerebrovascular disease and dementia including AD and CAA. Full article
(This article belongs to the Special Issue Vascular Signalling)
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18 pages, 3242 KiB  
Article
Involvement of NDPK-B in Glucose Metabolism-Mediated Endothelial Damage via Activation of the Hexosamine Biosynthesis Pathway and Suppression of O-GlcNAcase Activity
by Anupriya Chatterjee, Rachana Eshwaran, Gernot Poschet, Santosh Lomada, Mahmoud Halawa, Kerstin Wilhelm, Martina Schmidt, Hans-Peter Hammes, Thomas Wieland and Yuxi Feng
Cells 2020, 9(10), 2324; https://doi.org/10.3390/cells9102324 - 19 Oct 2020
Cited by 9 | Viewed by 2798
Abstract
Our previous studies identified that retinal endothelial damage caused by hyperglycemia or nucleoside diphosphate kinase-B (NDPK-B) deficiency is linked to elevation of angiopoietin-2 (Ang-2) and the activation of the hexosamine biosynthesis pathway (HBP). Herein, we investigated how NDPK-B is involved in the HBP [...] Read more.
Our previous studies identified that retinal endothelial damage caused by hyperglycemia or nucleoside diphosphate kinase-B (NDPK-B) deficiency is linked to elevation of angiopoietin-2 (Ang-2) and the activation of the hexosamine biosynthesis pathway (HBP). Herein, we investigated how NDPK-B is involved in the HBP in endothelial cells (ECs). The activities of NDPK-B and O-GlcNAcase (OGA) were measured by in vitro assays. Nucleotide metabolism and O-GlcNAcylated proteins were assessed by UPLC-PDA (Ultra-performance liquid chromatography with Photodiode array detection) and immunoblot, respectively. Re-expression of NDPK-B was achieved with recombinant adenoviruses. Our results show that NDPK-B depletion in ECs elevated UDP-GlcNAc levels and reduced NDPK activity, similar to high glucose (HG) treatment. Moreover, the expression and phosphorylation of glutamine:fructose-6-phosphate amidotransferase (GFAT) were induced, whereas OGA activity was suppressed. Furthermore, overall protein O-GlcNAcylation, along with O-GlcNAcylated Ang-2, was increased in NDPK-B depleted ECs. Pharmacological elevation of protein O-GlcNAcylation using Thiamet G (TMG) or OGA siRNA increased Ang-2 levels. However, the nucleoside triphosphate to diphosphate (NTP/NDP) transphosphorylase and histidine kinase activity of NDPK-B were dispensable for protein O-GlcNAcylation. NDPK-B deficiency hence results in the activation of HBP and the suppression of OGA activity, leading to increased protein O-GlcNAcylation and further upregulation of Ang-2. The data indicate a critical role of NDPK-B in endothelial damage via the modulation of the HBP. Full article
(This article belongs to the Special Issue Vascular Signalling)
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21 pages, 3895 KiB  
Article
Fibrotic Changes and Endothelial-to-Mesenchymal Transition Promoted by VEGFR2 Antagonism Alter the Therapeutic Effects of VEGFA Pathway Blockage in a Mouse Model of Choroidal Neovascularization
by Franco Aparecido Rossato, Yu Su, Ashley Mackey and Yin Shan Eric Ng
Cells 2020, 9(9), 2057; https://doi.org/10.3390/cells9092057 - 9 Sep 2020
Cited by 17 | Viewed by 3171
Abstract
Many patients with wet age-related macular degeneration do not respond well to anti- vascular endothelial growth factor A (VEGFA) therapy for choroidal neovascularization (CNV), and the efficacy of anti-VEGFA decreases over time. We investigated the hypothesis that fibrotic changes, in particular via endothelial-to-mesenchymal [...] Read more.
Many patients with wet age-related macular degeneration do not respond well to anti- vascular endothelial growth factor A (VEGFA) therapy for choroidal neovascularization (CNV), and the efficacy of anti-VEGFA decreases over time. We investigated the hypothesis that fibrotic changes, in particular via endothelial-to-mesenchymal transition (EndoMT), play a role in CNV and alter the therapeutic effects of VEGFA pathway blockage. Induction of EndoMT of primary human retinal endothelial cells led to a significantly reduced response to VEGFA at the level of gene expression, cellular proliferation, migration, and tube formation. Suppression of EndoMT restored cell responsiveness to VEGFA. In a mouse model of spontaneous CNV, fibrotic changes and EndoMT persisted as the CNV lesions became more established over time. VEGFA receptor-2 (VEGFR2) antagonism further induced fibrosis and EndoMT in the CNV. The combination of VEGFR2 antagonism and fibrosis/EndoMT inhibition was more effective than either individual treatment in reducing CNV. Our data indicate that fibrosis and EndoMT are involved in the progression of CNV, are exacerbated by VEGFR2 inhibition, and could provide an explanation for the reduced efficacy of anti-VEGFA treatment over time. Full article
(This article belongs to the Special Issue Vascular Signalling)
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19 pages, 3004 KiB  
Article
Protein Kinase CK2 Regulates Nerve/Glial Antigen (NG)2-Mediated Angiogenic Activity of Human Pericytes
by Beate M. Schmitt, Anne S. Boewe, Vivien Becker, Lisa Nalbach, Yuan Gu, Claudia Götz, Michael D. Menger, Matthias W. Laschke and Emmanuel Ampofo
Cells 2020, 9(6), 1546; https://doi.org/10.3390/cells9061546 - 25 Jun 2020
Cited by 9 | Viewed by 2902
Abstract
Protein kinase CK2 is a crucial regulator of endothelial cell proliferation, migration and sprouting during angiogenesis. However, it is still unknown whether this kinase additionally affects the angiogenic activity of other vessel-associated cells. In this study, we investigated the effect of CK2 inhibition [...] Read more.
Protein kinase CK2 is a crucial regulator of endothelial cell proliferation, migration and sprouting during angiogenesis. However, it is still unknown whether this kinase additionally affects the angiogenic activity of other vessel-associated cells. In this study, we investigated the effect of CK2 inhibition on primary human pericytes. We found that CK2 inhibition reduces the expression of nerve/glial antigen (NG)2, a crucial factor which is involved in angiogenic processes. Reporter gene assays revealed a 114 bp transcriptional active region of the human NG2 promoter, whose activity was decreased after CK2 inhibition. Functional analyses demonstrated that the pharmacological inhibition of CK2 by CX-4945 suppresses pericyte proliferation, migration, spheroid sprouting and the stabilization of endothelial tubes. Moreover, aortic rings of NG2−/− mice showed a significantly reduced vascular sprouting when compared to rings of NG2+/+ mice, indicating that NG2 is an important regulator of the angiogenic activity of pericytes. In vivo, implanted Matrigel plugs containing CX-4945-treated pericytes exhibited a lower microvessel density when compared to controls. These findings demonstrate that CK2 regulates the angiogenic activity of pericytes through NG2 gene expression. Hence, the inhibition of CK2 represents a promising anti-angiogenic strategy, because it does not only target endothelial cells, but also vessel-associated pericytes. Full article
(This article belongs to the Special Issue Vascular Signalling)
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17 pages, 5778 KiB  
Article
Elements of the Endomucin Extracellular Domain Essential for VEGF-Induced VEGFR2 Activity
by Zhengping Hu, Issahy Cano, Kahira L. Saez-Torres, Michelle E. LeBlanc, Magali Saint-Geniez, Yin-Shan Ng, Pablo Argüeso and Patricia A. D’Amore
Cells 2020, 9(6), 1413; https://doi.org/10.3390/cells9061413 - 5 Jun 2020
Cited by 11 | Viewed by 3544
Abstract
Endomucin (EMCN) is the type I transmembrane glycoprotein, mucin-like component of the endothelial cell glycocalyx. We have previously shown that EMCN is necessary for vascular endothelial growth factor (VEGF)-induced VEGF receptor 2 (VEGFR2) internalization and downstream signaling. To explore the structural components of [...] Read more.
Endomucin (EMCN) is the type I transmembrane glycoprotein, mucin-like component of the endothelial cell glycocalyx. We have previously shown that EMCN is necessary for vascular endothelial growth factor (VEGF)-induced VEGF receptor 2 (VEGFR2) internalization and downstream signaling. To explore the structural components of EMCN that are necessary for its function and the molecular mechanism of EMCN in VEGF-induced endothelial functions, we generated a series of mouse EMCN truncation mutants and examined their ability to rescue VEGF-induced endothelial functions in human primary endothelial cells (EC) in which endogenous EMCN had been knocked down using siRNA. Expression of the mouse full-length EMCN (FL EMCN) and the extracellular domain truncation mutants ∆21-81 EMCN and ∆21-121 EMCN, but not the shortest mutant ∆21-161 EMCN, successfully rescued the VEGF-induced EC migration, tube formation, and proliferation. ∆21-161 EMCN failed to interact with VEGFR2 and did not facilitate VEGFR2 internalization. Deletion of COSMC (C1GalT1C1) revealed that the abundant mucin-type O-glycans were not required for its VEGFR2-related functions. Mutation of the two N-glycosylation sites on ∆21-121 EMCN abolished its interaction with VEGFR2 and its function in VEGFR2 internalization. These results reveal ∆21-121 EMCN as the minimal extracellular domain sufficient for VEGFR2-mediated endothelial function and demonstrate an important role for N-glycosylation in VEGFR2 interaction, internalization, and angiogenic activity. Full article
(This article belongs to the Special Issue Vascular Signalling)
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23 pages, 24925 KiB  
Article
A Na,K-ATPase–Fodrin–Actin Membrane Cytoskeleton Complex is Required for Endothelial Fenestra Biogenesis
by Meihua Ju, Sofia Ioannidou, Peter Munro, Olli Rämö, Helena Vihinen, Eija Jokitalo and David T. Shima
Cells 2020, 9(6), 1387; https://doi.org/10.3390/cells9061387 - 3 Jun 2020
Cited by 6 | Viewed by 3263
Abstract
Fenestrae are transcellular plasma membrane pores that mediate blood–tissue exchange in specialised vascular endothelia. The composition and biogenesis of the fenestra remain enigmatic. We isolated and characterised the protein composition of large patches of fenestrated plasma membrane, termed sieve plates. Loss-of-function experiments demonstrated [...] Read more.
Fenestrae are transcellular plasma membrane pores that mediate blood–tissue exchange in specialised vascular endothelia. The composition and biogenesis of the fenestra remain enigmatic. We isolated and characterised the protein composition of large patches of fenestrated plasma membrane, termed sieve plates. Loss-of-function experiments demonstrated that two components of the sieve plate, moesin and annexin II, were positive and negative regulators of fenestra formation, respectively. Biochemical analyses showed that moesin is involved in the formation of an actin–fodrin submembrane cytoskeleton that was essential for fenestra formation. The link between the fodrin cytoskeleton and the plasma membrane involved the fenestral pore protein PV-1 and Na,K-ATPase, which is a key regulator of signalling during fenestra formation both in vitro and in vivo. These findings provide a conceptual framework for fenestra biogenesis, linking the dynamic changes in plasma membrane remodelling to the formation of a submembrane cytoskeletal signalling complex. Full article
(This article belongs to the Special Issue Vascular Signalling)
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22 pages, 4124 KiB  
Article
c-Jun, Foxo3a, and c-Myc Transcription Factors are Key Regulators of ATP-Mediated Angiogenic Responses in Pulmonary Artery Vasa Vasorum Endothelial Cells †
by Derek Strassheim, Vijaya Karoor, Hala Nijmeh, Philip Weston, Martin Lapel, Jerome Schaack, Timothy Sullivan, Edward C. Dempsey, Kurt R. Stenmark and Evgenia Gerasimovskaya
Cells 2020, 9(2), 416; https://doi.org/10.3390/cells9020416 - 11 Feb 2020
Cited by 9 | Viewed by 3828
Abstract
Angiogenic vasa vasorum (VV) expansion plays an essential role in the pathogenesis of hypoxia-induced pulmonary hypertension (PH), a cardiovascular disease. We previously showed that extracellular ATP released under hypoxic conditions is an autocrine/paracrine, the angiogenic factor for pulmonary artery (PA) VV endothelial cells [...] Read more.
Angiogenic vasa vasorum (VV) expansion plays an essential role in the pathogenesis of hypoxia-induced pulmonary hypertension (PH), a cardiovascular disease. We previously showed that extracellular ATP released under hypoxic conditions is an autocrine/paracrine, the angiogenic factor for pulmonary artery (PA) VV endothelial cells (VVECs), acting via P2Y purinergic receptors (P2YR) and the Phosphoinositide 3-kinase (PI3K)-Akt-Mammalian Target of Rapamycin (mTOR) signaling. To further elucidate the molecular mechanisms of ATP-mediated VV angiogenesis, we determined the profile of ATP-inducible transcription factors (TFs) in VVECs using a TranSignal protein/DNA array. C-Jun, c-Myc, and Foxo3 were found to be upregulated in most VVEC populations and formed nodes connecting several signaling networks. siRNA-mediated knockdown (KD) of these TFs revealed their critical role in ATP-induced VVEC angiogenic responses and the regulation of downstream targets involved in tissue remodeling, cell cycle control, expression of endothelial markers, cell adhesion, and junction proteins. Our results showed that c-Jun was required for the expression of ATP-stimulated angiogenic genes, c-Myc was repressive to anti-angiogenic genes, and Foxo3a predominantly controlled the expression of anti-apoptotic and junctional proteins. The findings from our study suggest that pharmacological targeting of the components of P2YR-PI3K-Akt-mTOR axis and specific TFs reduced ATP-mediated VVEC angiogenic response and may have a potential translational significance in attenuating pathological vascular remodeling. Full article
(This article belongs to the Special Issue Vascular Signalling)
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12 pages, 3001 KiB  
Article
Temporal Dynamics of VEGFA-Induced VEGFR2/FAK Co-Localization Depend on SHB
by Ilkka Pietilä, Djenolan Van Mourik, Andreas Tamelander, Vitezslav Kriz, Lena Claesson-Welsh, Anders Tengholm and Michael Welsh
Cells 2019, 8(12), 1645; https://doi.org/10.3390/cells8121645 - 15 Dec 2019
Cited by 12 | Viewed by 3637
Abstract
Focal adhesion kinase (FAK) is essential for vascular endothelial growth factor-A (VEGFA)/VEGF receptor-2 (VEGFR2)-stimulated angiogenesis and vascular permeability. We have previously noted that presence of the Src homology-2 domain adapter protein B (SHB) is of relevance for VEGFA-stimulated angiogenesis in a FAK-dependent manner. [...] Read more.
Focal adhesion kinase (FAK) is essential for vascular endothelial growth factor-A (VEGFA)/VEGF receptor-2 (VEGFR2)-stimulated angiogenesis and vascular permeability. We have previously noted that presence of the Src homology-2 domain adapter protein B (SHB) is of relevance for VEGFA-stimulated angiogenesis in a FAK-dependent manner. The current study was conducted in order address the temporal dynamics of co-localization between these components in HEK293 and primary lung endothelial cells (EC) by total internal reflection fluorescence microscopy (TIRF). An early (<2.5 min) VEGFA-induced increase in VEGFR2 co-localization with SHB was dependent on tyrosine 1175 in VEGFR2. VEGFA also enhanced SHB co-localization with FAK. FAK co-localization with VEGFR2 was dependent on SHB since it was significantly lower in SHB deficient EC after VEGFA addition. Absence of SHB also resulted in a gradual decline of VEGFR2 co-localization with FAK under basal (prior to VEGFA addition) conditions. A similar basal response was observed with expression of the Y1175F-VEGFR2 mutant in wild type EC. The distribution of focal adhesions in SHB-deficient EC was altered with a primarily perinuclear location. These live cell data implicate SHB as a key component regulating FAK activity in response to VEGFA/VEGFR2. Full article
(This article belongs to the Special Issue Vascular Signalling)
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Review

Jump to: Editorial, Research

27 pages, 4633 KiB  
Review
Cell–Matrix Interactions in the Eye: From Cornea to Choroid
by Andrew E. Pouw, Mark A. Greiner, Razek G. Coussa, Chunhua Jiao, Ian C. Han, Jessica M. Skeie, John H. Fingert, Robert F. Mullins and Elliott H. Sohn
Cells 2021, 10(3), 687; https://doi.org/10.3390/cells10030687 - 20 Mar 2021
Cited by 38 | Viewed by 8199
Abstract
The extracellular matrix (ECM) plays a crucial role in all parts of the eye, from maintaining clarity and hydration of the cornea and vitreous to regulating angiogenesis, intraocular pressure maintenance, and vascular signaling. This review focuses on the interactions of the ECM for [...] Read more.
The extracellular matrix (ECM) plays a crucial role in all parts of the eye, from maintaining clarity and hydration of the cornea and vitreous to regulating angiogenesis, intraocular pressure maintenance, and vascular signaling. This review focuses on the interactions of the ECM for homeostasis of normal physiologic functions of the cornea, vitreous, retina, retinal pigment epithelium, Bruch’s membrane, and choroid as well as trabecular meshwork, optic nerve, conjunctiva and tenon’s layer as it relates to glaucoma. A variety of pathways and key factors related to ECM in the eye are discussed, including but not limited to those related to transforming growth factor-β, vascular endothelial growth factor, basic-fibroblastic growth factor, connective tissue growth factor, matrix metalloproteinases (including MMP-2 and MMP-9, and MMP-14), collagen IV, fibronectin, elastin, canonical signaling, integrins, and endothelial morphogenesis consistent of cellular activation-tubulogenesis and cellular differentiation-stabilization. Alterations contributing to disease states such as wound healing, diabetes-related complications, Fuchs endothelial corneal dystrophy, angiogenesis, fibrosis, age-related macular degeneration, retinal detachment, and posteriorly inserted vitreous base are also reviewed. Full article
(This article belongs to the Special Issue Vascular Signalling)
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19 pages, 1380 KiB  
Review
Immune-Mediated Retinal Vasculitis in Posterior Uveitis and Experimental Models: The Leukotriene (LT)B4-VEGF Axis
by Malihe Eskandarpour, Miles A. Nunn, Wynne Weston-Davies and Virginia L. Calder
Cells 2021, 10(2), 396; https://doi.org/10.3390/cells10020396 - 15 Feb 2021
Cited by 5 | Viewed by 3461
Abstract
Retinal vascular diseases have distinct, complex and multifactorial pathogeneses yet share several key pathophysiological aspects including inflammation, vascular permeability and neovascularisation. In non-infectious posterior uveitis (NIU), retinal vasculitis involves vessel leakage leading to retinal enlargement, exudation, and macular oedema. Neovascularisation is not a [...] Read more.
Retinal vascular diseases have distinct, complex and multifactorial pathogeneses yet share several key pathophysiological aspects including inflammation, vascular permeability and neovascularisation. In non-infectious posterior uveitis (NIU), retinal vasculitis involves vessel leakage leading to retinal enlargement, exudation, and macular oedema. Neovascularisation is not a common feature in NIU, however, detection of the major angiogenic factor—vascular endothelial growth factor A (VEGF-A)—in intraocular fluids in animal models of uveitis may be an indication for a role for this cytokine in a highly inflammatory condition. Suppression of VEGF-A by directly targeting the leukotriene B4 (LTB4) receptor (BLT1) pathway indicates a connection between leukotrienes (LTs), which have prominent roles in initiating and propagating inflammatory responses, and VEGF-A in retinal inflammatory diseases. Further research is needed to understand how LTs interact with intraocular cytokines in retinal inflammatory diseases to guide the development of novel therapeutic approaches targeting both inflammatory mediator pathways. Full article
(This article belongs to the Special Issue Vascular Signalling)
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19 pages, 1189 KiB  
Review
The Role of BAR Proteins and the Glycocalyx in Brain Endothelium Transcytosis
by Diana M. Leite, Diana Matias and Giuseppe Battaglia
Cells 2020, 9(12), 2685; https://doi.org/10.3390/cells9122685 - 14 Dec 2020
Cited by 10 | Viewed by 4510
Abstract
Within the brain, endothelial cells lining the blood vessels meticulously coordinate the transport of nutrients, energy metabolites and other macromolecules essential in maintaining an appropriate activity of the brain. While small molecules are pumped across specialised molecular transporters, large macromolecular cargos are shuttled [...] Read more.
Within the brain, endothelial cells lining the blood vessels meticulously coordinate the transport of nutrients, energy metabolites and other macromolecules essential in maintaining an appropriate activity of the brain. While small molecules are pumped across specialised molecular transporters, large macromolecular cargos are shuttled from one side to the other through membrane-bound carriers formed by endocytosis on one side, trafficked to the other side and released by exocytosis. Such a process is collectively known as transcytosis. The brain endothelium is recognised to possess an intricate vesicular endosomal network that mediates the transcellular transport of cargos from blood-to-brain and brain-to-blood. However, mounting evidence suggests that brain endothelial cells (BECs) employ a more direct route via tubular carriers for a fast and efficient transport from the blood to the brain. Here, we compile the mechanism of transcytosis in BECs, in which we highlight intracellular trafficking mediated by tubulation, and emphasise the possible role in transcytosis of the Bin/Amphiphysin/Rvs (BAR) proteins and glycocalyx (GC)—a layer of sugars covering BECs, in transcytosis. Both BAR proteins and the GC are intrinsically associated with cell membranes and involved in the modulation and shaping of these membranes. Hence, we aim to summarise the machinery involved in transcytosis in BECs and highlight an uncovered role of BAR proteins and the GC at the brain endothelium. Full article
(This article belongs to the Special Issue Vascular Signalling)
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23 pages, 1321 KiB  
Review
Capillary Rarefaction in Obesity and Metabolic Diseases—Organ-Specificity and Possible Mechanisms
by Satu Paavonsalo, Sangeetha Hariharan, Madeleine H. Lackman and Sinem Karaman
Cells 2020, 9(12), 2683; https://doi.org/10.3390/cells9122683 - 14 Dec 2020
Cited by 38 | Viewed by 5039
Abstract
Obesity and its comorbidities like diabetes, hypertension and other cardiovascular disorders are the leading causes of death and disability worldwide. Metabolic diseases cause vascular dysfunction and loss of capillaries termed capillary rarefaction. Interestingly, obesity seems to affect capillary beds in an organ-specific manner, [...] Read more.
Obesity and its comorbidities like diabetes, hypertension and other cardiovascular disorders are the leading causes of death and disability worldwide. Metabolic diseases cause vascular dysfunction and loss of capillaries termed capillary rarefaction. Interestingly, obesity seems to affect capillary beds in an organ-specific manner, causing morphological and functional changes in some tissues but not in others. Accordingly, treatment strategies targeting capillary rarefaction result in distinct outcomes depending on the organ. In recent years, organ-specific vasculature and endothelial heterogeneity have been in the spotlight in the field of vascular biology since specialized vascular systems have been shown to contribute to organ function by secreting varying autocrine and paracrine factors and by providing niches for stem cells. This review summarizes the recent literature covering studies on organ-specific capillary rarefaction observed in obesity and metabolic diseases and explores the underlying mechanisms, with multiple modes of action proposed. It also provides a glimpse of the reported therapeutic perspectives targeting capillary rarefaction. Further studies should address the reasons for such organ-specificity of capillary rarefaction, investigate strategies for its prevention and reversibility and examine potential signaling pathways that can be exploited to target it. Full article
(This article belongs to the Special Issue Vascular Signalling)
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40 pages, 2542 KiB  
Review
Signalling, Metabolic Pathways and Iron Homeostasis in Endothelial Cells in Health, Atherosclerosis and Alzheimer’s Disease
by Emy Bosseboeuf and Claudio Raimondi
Cells 2020, 9(9), 2055; https://doi.org/10.3390/cells9092055 - 8 Sep 2020
Cited by 25 | Viewed by 5249
Abstract
Endothelial cells drive the formation of new blood vessels in physiological and pathological contexts such as embryonic development, wound healing, cancer and ocular diseases. Once formed, all vessels of the vasculature system present an endothelial monolayer (the endothelium), lining the luminal wall of [...] Read more.
Endothelial cells drive the formation of new blood vessels in physiological and pathological contexts such as embryonic development, wound healing, cancer and ocular diseases. Once formed, all vessels of the vasculature system present an endothelial monolayer (the endothelium), lining the luminal wall of the vessels, that regulates gas and nutrient exchange between the circulating blood and tissues, contributing to maintaining tissue and vascular homeostasis. To perform their functions, endothelial cells integrate signalling pathways promoted by growth factors, cytokines, extracellular matrix components and signals from mechanosensory complexes sensing the blood flow. New evidence shows that endothelial cells rely on specific metabolic pathways for distinct cellular functions and that the integration of signalling and metabolic pathways regulates endothelial-dependent processes such as angiogenesis and vascular homeostasis. In this review, we provide an overview of endothelial functions and the recent advances in understanding the role of endothelial signalling and metabolism in physiological processes such as angiogenesis and vascular homeostasis and vascular diseases. Also, we focus on the signalling pathways promoted by the transmembrane protein Neuropilin-1 (NRP1) in endothelial cells, its recently discovered role in regulating mitochondrial function and iron homeostasis and the role of mitochondrial dysfunction and iron in atherosclerosis and neurodegenerative diseases. Full article
(This article belongs to the Special Issue Vascular Signalling)
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33 pages, 4145 KiB  
Review
It Takes Two to Tango: Endothelial TGFβ/BMP Signaling Crosstalk with Mechanobiology
by Christian Hiepen, Paul-Lennard Mendez and Petra Knaus
Cells 2020, 9(9), 1965; https://doi.org/10.3390/cells9091965 - 26 Aug 2020
Cited by 30 | Viewed by 7635
Abstract
Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGFβ) superfamily of cytokines. While some ligand members are potent inducers of angiogenesis, others promote vascular homeostasis. However, the precise understanding of the molecular mechanisms underlying these functions is still a growing [...] Read more.
Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGFβ) superfamily of cytokines. While some ligand members are potent inducers of angiogenesis, others promote vascular homeostasis. However, the precise understanding of the molecular mechanisms underlying these functions is still a growing research field. In bone, the tissue in which BMPs were first discovered, crosstalk of TGFβ/BMP signaling with mechanobiology is well understood. Likewise, the endothelium represents a tissue that is constantly exposed to multiple mechanical triggers, such as wall shear stress, elicited by blood flow or strain, and tension from the surrounding cells and to the extracellular matrix. To integrate mechanical stimuli, the cytoskeleton plays a pivotal role in the transduction of these forces in endothelial cells. Importantly, mechanical forces integrate on several levels of the TGFβ/BMP pathway, such as receptors and SMADs, but also global cell-architecture and nuclear chromatin re-organization. Here, we summarize the current literature on crosstalk mechanisms between biochemical cues elicited by TGFβ/BMP growth factors and mechanical cues, as shear stress or matrix stiffness that collectively orchestrate endothelial function. We focus on the different subcellular compartments in which the forces are sensed and integrated into the TGFβ/BMP growth factor signaling. Full article
(This article belongs to the Special Issue Vascular Signalling)
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19 pages, 716 KiB  
Review
The State of Art of Regenerative Therapy in Cardiovascular Ischemic Disease: Biology, Signaling Pathways, and Epigenetics of Endothelial Progenitor Cells
by Fabio Perrotta, Angelica Perna, Klara Komici, Ersilia Nigro, Mariano Mollica, Vito D’Agnano, Antonio De Luca and Germano Guerra
Cells 2020, 9(8), 1886; https://doi.org/10.3390/cells9081886 - 11 Aug 2020
Cited by 19 | Viewed by 3258
Abstract
Ischemic heart disease is currently a major cause of mortality and morbidity worldwide. Nevertheless, the actual therapeutic scenario does not target myocardial cell regeneration and consequently, the progression toward the late stage of chronic heart failure is common. Endothelial progenitor cells (EPCs) are [...] Read more.
Ischemic heart disease is currently a major cause of mortality and morbidity worldwide. Nevertheless, the actual therapeutic scenario does not target myocardial cell regeneration and consequently, the progression toward the late stage of chronic heart failure is common. Endothelial progenitor cells (EPCs) are bone marrow-derived stem cells that contribute to the homeostasis of the endothelial wall in acute and chronic ischemic disease. Calcium modulation and other molecular pathways (NOTCH, VEGFR, and CXCR4) contribute to EPC proliferation and differentiation. The present review provides a summary of EPC biology with a particular focus on the regulatory pathways of EPCs and describes promising applications for cardiovascular cell therapy. Full article
(This article belongs to the Special Issue Vascular Signalling)
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29 pages, 3158 KiB  
Review
Endothelial TRPV1 as an Emerging Molecular Target to Promote Therapeutic Angiogenesis
by Sharon Negri, Pawan Faris, Vittorio Rosti, Maria Rosa Antognazza, Francesco Lodola and Francesco Moccia
Cells 2020, 9(6), 1341; https://doi.org/10.3390/cells9061341 - 27 May 2020
Cited by 37 | Viewed by 6495
Abstract
Therapeutic angiogenesis represents an emerging strategy to treat ischemic diseases by stimulating blood vessel growth to rescue local blood perfusion. Therefore, injured microvasculature may be repaired by stimulating resident endothelial cells or circulating endothelial colony forming cells (ECFCs) or by autologous cell-based therapy. [...] Read more.
Therapeutic angiogenesis represents an emerging strategy to treat ischemic diseases by stimulating blood vessel growth to rescue local blood perfusion. Therefore, injured microvasculature may be repaired by stimulating resident endothelial cells or circulating endothelial colony forming cells (ECFCs) or by autologous cell-based therapy. Endothelial Ca2+ signals represent a crucial player in angiogenesis and vasculogenesis; indeed, several angiogenic stimuli induce neovessel formation through an increase in intracellular Ca2+ concentration. Several members of the Transient Receptor Potential (TRP) channel superfamily are expressed and mediate Ca2+-dependent functions in vascular endothelial cells and in ECFCs, the only known truly endothelial precursor. TRP Vanilloid 1 (TRPV1), a polymodal cation channel, is emerging as an important player in endothelial cell migration, proliferation, and tubulogenesis, through the integration of several chemical stimuli. Herein, we first summarize TRPV1 structure and gating mechanisms. Next, we illustrate the physiological roles of TRPV1 in vascular endothelium, focusing our attention on how endothelial TRPV1 promotes angiogenesis. In particular, we describe a recent strategy to stimulate TRPV1-mediated pro-angiogenic activity in ECFCs, in the presence of a photosensitive conjugated polymer. Taken together, these observations suggest that TRPV1 represents a useful target in the treatment of ischemic diseases. Full article
(This article belongs to the Special Issue Vascular Signalling)
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21 pages, 1082 KiB  
Review
Microglia Contribution to the Regulation of the Retinal and Choroidal Vasculature in Age-Related Macular Degeneration
by C. Henrique Alves, Rosa Fernandes, Ana Raquel Santiago and António Francisco Ambrósio
Cells 2020, 9(5), 1217; https://doi.org/10.3390/cells9051217 - 14 May 2020
Cited by 36 | Viewed by 5999
Abstract
The retina is a highly metabolically active tissue with high-level consumption of nutrients and oxygen. This high metabolic demand requires a properly developed and maintained vascular system. The retina is nourished by two systems: the central retinal artery that supplies the inner retina [...] Read more.
The retina is a highly metabolically active tissue with high-level consumption of nutrients and oxygen. This high metabolic demand requires a properly developed and maintained vascular system. The retina is nourished by two systems: the central retinal artery that supplies the inner retina and the choriocapillaris that supplies the outer retina and retinal pigment epithelium (RPE). Pathological neovascularization, characterized by endothelial cell proliferation and new vessel formation, is a common hallmark in several retinal degenerative diseases, including age-related macular degeneration (AMD). A limited number of studies have suggested that microglia, the resident immune cells of the retina, have an important role not only in the pathology but also in the formation and physiology of the retinal vascular system. Here, we review the current knowledge on microglial interaction with the retinal vascular system under physiological and pathological conditions. To do so, we first highlight the role of microglial cells in the formation and maintenance of the retinal vasculature system. Thereafter, we discuss the molecular signaling mechanisms through which microglial cells contribute to the alterations in retinal and choroidal vasculatures and to the neovascularization in AMD. Full article
(This article belongs to the Special Issue Vascular Signalling)
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