p120-catenin and β-catenin differentially regulate cadherin adhesive function

Vascular endothelial (VE)-cadherin, the major adherens junction adhesion molecule in endothelial cells, interacts with p120-catenin and β-catenin through its cytoplasmic tail. However, the specific functional contributions of the catenins to the establishment of strong adhesion are not fully understood. Here we use bioengineering approaches to identify the roles of cadherin–catenin interactions in promoting strong cellular adhesion and the ability of the cells to spread on an adhesive surface. Our results demonstrate that the domain of VE-cadherin that binds to β-catenin is required for the establishment of strong steady-state adhesion strength. Surprisingly, p120 binding to the cadherin tail had no effect on the strength of adhesion when the available adhesive area was limited. Instead, the binding of VE-cadherin to p120 regulates adhesive contact area in a Rac1-dependent manner. These findings reveal that p120 and β-catenin have distinct but complementary roles in strengthening cadherin-mediated adhesion.

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Biomechanical interactions of Schistosoma mansoni eggs with vascular endothelial cells facilitate egg extravasation

10.1101/2021.09.16.459846 ◽

2021 ◽

Author(s):

Yi-Ting Yeh ◽

Danielle E. Skinner ◽

Ernesto Criado-Hidalgo ◽

Natalie Shee Chen ◽

Antoni Garcia-De Herreros ◽

...

Keyword(s):

Endothelial Cells ◽

Schistosoma Mansoni ◽

Disease Transmission ◽

Vascular Endothelial Cells ◽

Flexible Substrate ◽

Blood Stream ◽

The Body ◽

Dependent Manner ◽

Vascular Endothelial ◽

Maturation State

AbstractThe eggs of the parasitic blood fluke, Schistosoma, are the main drivers of the chronic pathologies associated with schistosomiasis, a disease of poverty afflicting approximately 220 million people worldwide. Eggs laid by Schistosoma mansoni in the bloodstream of the host are encapsulated by vascular endothelial cells (VECs), the first step in the migration of the egg from the blood stream into the lumen of the gut and eventual exit from the body. The biomechanics associated with encapsulation and extravasation of the egg are poorly understood. We demonstrate that S. mansoni eggs induce VECs to form two types of membrane extensions during encapsulation; filopodia that probe eggshell surfaces and intercellular nanotubes that presumably facilitate VEC communication. Encapsulation efficiency, the number of filopodia and intercellular nanotubes, and the length of these structures depend on the egg’s vitality and, to a lesser degree, its maturation state. During encapsulation, live eggs induce VEC contractility and membranous structures formation, in a Rho/ROCK pathway-dependent manner. Using elastic hydrogels embedded with fluorescent microbeads as substrates to culture VECs, live eggs induce VECs to exert significantly greater contractile forces during encapsulation than dead eggs, which leads to 3D deformations on both the VEC monolayer and the flexible substrate underneath. These significant mechanical deformations cause the VEC monolayer tension to fluctuate with eventual rupture of VEC junctions, thus facilitating egg transit out of the blood vessel. Overall, our data on the mechanical interplay between host VECs and the schistosome egg improve our understanding of how this parasite manipulates its immediate environment to maintain disease transmission.

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Citrus bergamiaRisso Elevates Intracellular Ca2+in Human Vascular Endothelial Cells due to Release of Ca2+from Primary Intracellular Stores

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/759615 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Purum Kang ◽

Seung Ho Han ◽

Hea Kyung Moon ◽

Jeong-Min Lee ◽

Hyo-Keun Kim ◽

...

Keyword(s):

Endothelial Cells ◽

Channel Blocker ◽

Vascular Endothelial Cells ◽

Umbilical Vein ◽

Dependent Manner ◽

Vascular Endothelial ◽

Concentration Dependent Manner ◽

Carbonyl Cyanide ◽

Intracellular Ca ◽

Umbilical Vein Endothelial Cells

The purpose of the present study is to examine the effects of essential oil ofCitrus bergamiaRisso (bergamot, BEO) on intracellular Ca2+in human umbilical vein endothelial cells. Fura-2 fluorescence was used to examine changes in intracellular Ca2+concentration[Ca2+]i. In the presence of extracellular Ca2+, BEO increased[Ca2+]i, which was partially inhibited by a nonselective Ca2+channel blocker La3+. In Ca2+-free extracellular solutions, BEO increased[Ca2+]iin a concentration-dependent manner, suggesting that BEO mobilizes intracellular Ca2+. BEO-induced[Ca2+]iincrease was partially inhibited by a Ca2+-induced Ca2+release inhibitor dantrolene, a phospholipase C inhibitor U73122, and an inositol 1,4,5-triphosphate (IP3)-gated Ca2+channel blocker, 2-aminoethoxydiphenyl borane (2-APB). BEO also increased[Ca2+]iin the presence of carbonyl cyanide m-chlorophenylhydrazone, an inhibitor of mitochondrial Ca2+uptake. In addition, store-operated Ca2+entry (SOC) was potentiated by BEO. These results suggest that BEO mobilizes Ca2+from primary intracellular stores via Ca2+-induced and IP3-mediated Ca2+release and affect promotion of Ca2+influx, likely via an SOC mechanism.

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Exchange Protein Directly Activated by cAMP Modulates Ebola Virus Uptake into Vascular Endothelial Cells

Viruses ◽

10.3390/v10100563 ◽

2018 ◽

Vol 10 (10) ◽

pp. 563 ◽

Cited By ~ 5

Author(s):

Aleksandra Drelich ◽

Barbara Judy ◽

Xi He ◽

Qing Chang ◽

Shangyi Yu ◽

...

Keyword(s):

Endothelial Cells ◽

Ebola Virus ◽

Vascular Endothelial Cells ◽

Ex Vivo ◽

Marburg Virus ◽

Dependent Manner ◽

Vascular Endothelial ◽

Ultrastructural Studies ◽

Ebov Infection ◽

Exchange Protein

Members of the family Filoviridae, including Ebola virus (EBOV) and Marburg virus (MARV), cause severe hemorrhagic fever in humans and nonhuman primates. Given their high lethality, a comprehensive understanding of filoviral pathogenesis is urgently needed. In the present studies, we revealed that the exchange protein directly activated by cAMP 1 (EPAC1) gene deletion protects vasculature in ex vivo explants from EBOV infection. Importantly, pharmacological inhibition of EPAC1 using EPAC-specific inhibitors (ESIs) mimicked the EPAC1 knockout phenotype in the ex vivo model. ESI treatment dramatically decreased EBOV infectivity in both ex vivo vasculature and in vitro vascular endothelial cells (ECs). Furthermore, postexposure protection of ECs against EBOV infection was conferred using ESIs. Protective efficacy of ESIs in ECs was observed also in MARV infection. Additional studies using a vesicular stomatitis virus pseudotype that expresses EBOV glycoprotein (EGP-VSV) confirmed that ESIs reduced infection in ECs. Ultrastructural studies suggested that ESIs blocked EGP-VSV internalization via inhibition of macropinocytosis. The inactivation of EPAC1 affects the early stage of viral entry after viral binding to the cell surface, but before early endosome formation, in a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-dependent manner. Our study delineated a new critical role of EPAC1 during EBOV uptake into ECs.

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Characterization of the vasculogenic block in the absence of vascular endothelial growth factor-A

Blood ◽

10.1182/blood.v95.6.1979 ◽

2000 ◽

Vol 95 (6) ◽

pp. 1979-1987 ◽

Cited By ~ 35

Author(s):

Victoria L. Bautch ◽

Sambra D. Redick ◽

Aaron Scalia ◽

Marco Harmaty ◽

Peter Carmeliet ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Embryonic Stem ◽

Dependent Manner ◽

Vascular Endothelial ◽

Vegf Signaling ◽

Homozygous Mutant ◽

Endothelial Growth Factor ◽

Rna Levels

Abstract Vascular endothelial growth factor (VEGF) signaling is required for both differentiation and proliferation of vascular endothelium. Analysis of differentiated embryonic stem cells with one or both VEGF-A alleles deleted showed that both the differentiation and the expansion of endothelial cells are blocked during vasculogenesis. Blood island formation was reduced by half in hemizygous mutant VEGF cultures and by 10-fold in homozygous mutant VEGF cultures. Homozygous mutant cultures could be partially rescued by the addition of exogenous VEGF. RNA levels for the endothelial adhesion receptors ICAM-2 and PECAM were reduced in homozygous mutant cultures, but ICAM-2 RNA levels decreased substantially, whereas PECAM RNA levels remained at hemizygous levels. The quantitative data correlated with the antibody staining patterns because cells that were not organized into vessels expressed PECAM but not ICAM-2. These PECAM+ cell clumps accumulated in mutant cultures as vessel density decreased, suggesting that they were endothelial cell precursors blocked from maturation. A subset of PECAM+ cells in clumps expressed stage-specific embryonic antigen-1 (SSEA-1), and all were ICAM-2(−) and CD34(−), whereas vascular endothelial cells incorporated into vessels were PECAM(+), ICAM-2(+), CD34(+), and SSEA-1(−). Analysis of flk-1 expression indicated that a subset of vascular precursor cells coexpressed PECAM and flk-1. These data suggest that VEGF signaling acts in a dose-dependent manner to affect both a specific differentiation step and the subsequent expansion of endothelial cells.

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Imbalanced Production of Reactive Oxygen Species and Mitochondrial Antioxidant SOD2 in Fabry Disease-Specific Human Induced Pluripotent Stem Cell-Differentiated Vascular Endothelial Cells

Cell Transplantation ◽

10.3727/096368916x694265 ◽

2017 ◽

Vol 26 (3) ◽

pp. 513-527 ◽

Cited By ~ 18

Author(s):

Wei-Lien Tseng ◽

Shih-Jie Chou ◽

Huai-Chih Chiang ◽

Mong-Lien Wang ◽

Chian-Shiu Chien ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Endothelial Cells ◽

Fabry Disease ◽

Reactive Oxygen ◽

Dependent Manner ◽

Vascular Endothelial ◽

Ros Production ◽

Oxygen Species ◽

Ampk Activity ◽

Induced Pluripotent

Fabry disease (FD) is an X-linked inherited lysosomal storage disease caused by α-galactosidase A (GLA) deficiency. Progressive intracellular accumulation of globotriaosylceramide (Gb3) is considered to be pathogenically responsible for the phenotype variability of FD that causes cardiovascular dysfunction; however, molecular mechanisms underlying the impairment of FD-associated cardiovascular tissues remain unclear. In this study, we reprogrammed human induced pluripotent stem cells (hiPSCs) from peripheral blood cells of patients with FD (FD-iPSCs); subsequently differentiated them into vascular endothelial-like cells (FD-ECs) expressing CD31, VE-cadherin, and vWF; and investigated their ability to form vascular tube-like structures. FD-ECs recapitulated the FD pathophysiological phenotype exhibiting intracellular Gb3 accumulation under a transmission electron microscope. Moreover, compared with healthy control iPSC-derived endothelial cells (NC-ECs), reactive oxygen species (ROS) production considerably increased in FD-ECs. Microarray analysis was performed to explore the possible mechanism underlying Gb3 accumulation-induced ROS production in FD-ECs. Our results revealed that superoxide dismutase 2 (SOD2), a mitochondrial antioxidant, was significantly downregulated in FD-ECs. Compared with NC-ECs, AMPK activity was significantly enhanced in FD-ECs. Furthermore, to investigate the role of Gb3 in these effects, human umbilical vein endothelial cells (HUVECs) were treated with Gb3. After Gb3 treatment, we observed that SOD2 expression was suppressed and AMPK activity was enhanced in a dose-dependent manner. Collectively, our results indicate that excess accumulation of Gb3 suppressed SOD2 expression, increased ROS production, enhanced AMPK activation, and finally caused vascular endothelial dysfunction. Our findings suggest that dysregulated mitochondrial ROS may be a potential target for treating FD.

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Hypoxia induces autophagy in human vascular endothelial cells in a hypoxia-inducible factor 1-dependent manner

Molecular Medicine Reports ◽

10.3892/mmr.2014.3093 ◽

2014 ◽

Vol 11 (4) ◽

pp. 2677-2682 ◽

Cited By ~ 9

Author(s):

JIANBO WU ◽

ZHEN LEI ◽

JINGUI YU

Keyword(s):

Endothelial Cells ◽

Vascular Endothelial Cells ◽

Hypoxia Inducible Factor ◽

Dependent Manner ◽

Vascular Endothelial ◽

Hypoxia Inducible Factor 1

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Akt Mediates Cytoprotection of Endothelial Cells by Vascular Endothelial Growth Factor in an Anchorage-dependent Manner

Journal of Biological Chemistry ◽

10.1074/jbc.274.23.16349 ◽

1999 ◽

Vol 274 (23) ◽

pp. 16349-16354 ◽

Cited By ~ 415

Author(s):

Yasushi Fujio ◽

Kenneth Walsh

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Dependent Manner ◽

Vascular Endothelial ◽

Endothelial Growth Factor

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High-mobility group box 1 protein induces tissue factor expression in vascular endothelial cells via activation of NF-κB and Egr-1

Thrombosis and Haemostasis ◽

10.1160/th08-11-0759 ◽

2009 ◽

Vol 102 (08) ◽

pp. 352-359 ◽

Cited By ~ 29

Author(s):

Haichao Wang ◽

Yiting Tang ◽

Zhang Fan ◽

Ben Lv ◽

Xianzhong Xiao ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Surface ◽

Tissue Factor ◽

Vascular Endothelial Cells ◽

High Mobility ◽

High Mobility Group ◽

Cell Surface Receptors ◽

Dependent Manner ◽

Vascular Endothelial ◽

Surface Receptors

SummaryHigh-mobility group box 1 protein (HMGB1), an abundant nuclear protein, was recently established as a proinflammatory mediator of experimental sepsis.Although extracellular HMGB1 has been found in atherosclerotic plaques, its potential role in the pathogenesis of atherothrombosis remains elusive. In the present study, we determined whether HMGB1 induces tissue factor (TF) expression in vascular endothelial cells (ECs) and macrophages. Our data showed that HMGB1 stimulated ECs to express TF (but not TF pathway inhibitor) mRNA and protein in a concentration and time-dependent manner. Blockade of cell surface receptors (including TLR4, TLR2, and RAGE) with specific neutralising antibodies partially reduced HMGB1-induced TF expression. Moreover, HMGB1 increased expression of Egr-1 and nuclear translocation of NF-κB (c-Rel/p65) in ECs. Taken together, our data suggest that HMGB1 induces TF expression in vascular endothelial cells via cell surface receptors (TLR4, TLR2, and RAGE), and through activation of transcription factors (NF-κB and Egr-1).

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