scholarly journals Zinc regulates vascular endothelial cell activity through zinc-sensing receptor ZnR/GPR39

2018 ◽  
Vol 314 (4) ◽  
pp. C404-C414 ◽  
Author(s):  
Donghui Zhu ◽  
Yingchao Su ◽  
Yufeng Zheng ◽  
Bingmei Fu ◽  
Liping Tang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Cell Survival ◽  
Vascular Tone ◽  
Cell Activity ◽  
Heme Oxygenase 1 ◽  
Dependent Manner ◽  
Vascular Endothelial

Zn2+ is an essential element for cell survival/growth, and its deficiency is linked to many disorders. Extracellular Zn2+ concentration changes participate in modulating fundamental cellular processes such as proliferation, secretion, ion transport, and cell signal transduction in a mechanism that is not well understood. Here, we hypothesize that the Zn2+-sensing receptor ZnR/G protein-coupled receptor 39 (GPR39), found in tissues where dynamic Zn2+ homeostasis takes place, enables extracellular Zn2+ to trigger intracellular signaling pathways regulating key cell functions in vascular cells. Thus, we investigated how extracellular Zn2+ regulates cell viability, proliferation, motility, angiogenesis, vascular tone, and inflammation through ZnR/GPR39 in endothelial cells. Knockdown of GPR39 through siRNA largely abolished Zn2+-triggered cellular activity changes, Ca2+ responses, as well as the downstream activation of Gαq-PLC pathways. Extracellular Zn2+ promoted vascular cell survival/growth through activation of cAMP and Akt as well as overexpressing of platelet-derived growth factor-α receptor and vascular endothelial growth factor A. It also enhanced cell adhesion and mobility, endothelial tubule formation, and cytoskeletal reorganization. Such effects from extracellular Zn2+ were not observed in GPR39−/− endothelial cells. Zn2+ also regulated inflammation-related key molecules such as heme oxygenase-1, selectin L, IL-10, and platelet endothelial cell adhesion molecule 1, as well as vascular tone-related prostaglandin I2 synthase and nitric oxide synthase-3. In sum, extracellular Zn2+ regulates endothelial cell activity in a ZnR/GPR39-dependent manner and through the downstream Gαq-PLC pathways. Thus, ZnR/GPR39 may be a therapeutic target for regulating endothelial activity.

A proangiogenic peptide derived from vascular endothelial growth factor receptor-1 acts through α5β1 integrin

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3479-3488 ◽  
Author(s):  
Simonetta Soro ◽  
Angela Orecchia ◽  
Lucia Morbidelli ◽  
Pedro Miguel Lacal ◽  
Veronica Morea ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
Growth Factors ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor ◽  
Α5β1 Integrin

Abstract Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor for growth factors of the VEGF family. Endothelial cells express a membrane-bound and a soluble variant of this protein, the latter being mainly considered as a negative regulator of VEGF-A signaling. We previously reported that the soluble form is deposited in the extracellular matrix produced by endothelial cells in culture and is able to promote cell adhesion and migration through binding to α5β1 integrin. In this study, we demonstrate that the Ig-like domain II of VEGFR-1, which contains the binding determinants for the growth factors, is involved in the interaction with α5β1 integrin. To identify domain regions involved in integrin binding, we designed 12 peptides putatively mimicking the domain II surface and tested their ability to inhibit α5β1-mediated endothelial cell adhesion to soluble VEGFR-1 and directly support cell adhesion. One peptide endowed with both these properties was identified and shown to inhibit endothelial cell migration toward soluble VEGFR-1 as well. This peptide directly binds α5β1 integrin, but not VEGF-A, inducing endothelial cell tubule formation in vitro and neoangiogenesis in vivo. Alanine scanning mutagenesis of the peptide defined which residues were responsible for its biologic activity and integrin binding.

Intracisternal administration of transforming growth factor-β evokes fever through the induction of cyclooxygenase-2 in brain endothelial cells

2008 ◽  
Vol 294 (1) ◽  
pp. R266-R275 ◽  
Author(s):  
Shigenobu Matsumura ◽  
Tetsuro Shibakusa ◽  
Teppei Fujikawa ◽  
Hiroyuki Yamada ◽  
Kiyoshi Matsumura ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Proinflammatory Cytokines ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cyclooxygenase 2 ◽  
Dependent Manner ◽  
Cox 2 ◽  
Β Receptor

Transforming growth factor-β (TGF-β), a pleiotropic cytokine, regulates cell proliferation, differentiation, and apoptosis, and plays a key role in development and tissue homeostasis. TGF-β functions as an anti-inflammatory cytokine because it suppresses microglia and B-lymphocyte functions, as well as the production of proinflammatory cytokines. However, we previously demonstrated that the intracisternal administration of TGF-β induces fever like that produced by proinflammatory cytokines. In this study, we investigated the mechanism of TGF-β-induced fever. The intracisternal administration of TGF-β increased body temperature in a dose-dependent manner. Pretreatment with cyclooxygenase-2 (COX-2)-selective inhibitor significantly suppressed TGF-β-induced fever. COX-2 is known as one of the rate-limiting enzymes of the PGE2 synthesis pathway, suggesting that fever induced by TGF-β is COX-2 and PGE2 dependent. TGF-β increased PGE2 levels in cerebrospinal fluid and increased the expression of COX-2 in the brain. Double immunostaining of COX-2 and von Willebrand factor (vWF, an endothelial cell marker) revealed that COX-2-expressing cells were mainly endothelial cells. Although not all COX-2-immunoreactive cells express TGF-β receptor, some COX-2-immunoreactive cells express activin receptor-like kinase-1 (ALK-1, an endothelial cell-specific TGF-β receptor), suggesting that TGF-β directly or indirectly acts on endothelial cells to induce COX-2 expression. These findings suggest a novel function of TGF-β as a proinflammatory cytokine in the central nervous system.

scholarly journals Mid-luteal angiogenesis and function in the primate is dependent on vascular endothelial growth factor

2001 ◽  
Vol 168 (3) ◽  
pp. 409-416 ◽  
Author(s):  
SE Dickson ◽  
R Bicknell ◽  
HM Fraser
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Luteal Phase ◽  
Smooth Muscle Actin ◽  
Proliferation Index ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is essential for the angiogenesis required for the formation of the corpus luteum; however, its role in ongoing luteal angiogenesis and in the maintenance of the established vascular network is unknown. The aim of this study was to determine whether VEGF inhibition could intervene in ongoing luteal angiogenesis using immunoneutralisation of VEGF starting in the mid-luteal phase. In addition, the effects on endothelial cell survival and the recruitment of periendothelial support cells were examined. Treatment with a monoclonal antibody to VEGF, or mouse gamma globulin for control animals, commenced on day 7 after ovulation and continued for 3 days. Bromodeoxyuridine (BrdU), used to label proliferating cells to obtain a proliferation index, was administered one hour before collecting ovaries from control and treated animals. Ovarian sections were stained using antibodies to BrdU, the endothelial cell marker, CD31, the pericyte marker, alpha-smooth muscle actin, and 3' end DNA fragments as a marker for apoptosis. VEGF immunoneutralisation significantly suppressed endothelial cell proliferation and the area occupied by endothelial cells while increasing pericyte coverage and the incidence of endothelial cell apoptosis. Luteal function was markedly compromised by anti-VEGF treatment as judged by a 50% reduction in plasma progesterone concentration. It is concluded that ongoing angiogenesis in the mid-luteal phase is primarily driven by VEGF, and that a proportion of endothelial cells of the mid-luteal phase vasculature are dependent on VEGF support.

scholarly journals Maturation of Embryonic Stem Cells Into Endothelial Cells in an In Vitro Model of Vasculogenesis

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1253-1263 ◽  
Author(s):  
Masanori Hirashima ◽  
Hiroshi Kataoka ◽  
Satomi Nishikawa ◽  
Norihisa Matsuyoshi ◽  
Shin-Ichi Nishikawa
Keyword(s):  
Cell Adhesion ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Culture System ◽  
Molecular Mechanisms ◽  
Es Cells ◽  
Embryonic Stem ◽  
Vascular Endothelial ◽  
Cell Cell

A primitive vascular plexus is formed through coordinated regulation of differentiation, proliferation, migration, and cell-cell adhesion of endothelial cell (EC) progenitors. In this study, a culture system was devised to investigate the behavior of purified EC progenitors in vitro. Because Flk-1+ cells derived from ES cells did not initially express other EC markers, they were sorted and used as EC progenitors. Their in vitro differentiation into ECs, via vascular endothelial-cadherin (VE-cadherin)+ platelet-endothelial cell adhesion molecule-1 (PECAM-1)+ CD34−to VE-cadherin+ PECAM-1+CD34+ stage, occurred without exogenous factors, whereas their proliferation, particularly at low cell density, required OP9 feeder cells. On OP9 feeder layer, EC progenitors gave rise to sheet-like clusters of Flk-1+ cells, with VE-cadherin concentrated at the cell-cell junction. The growth was suppressed by Flt-1-IgG1 chimeric protein and dependent on vascular endothelial growth factor (VEGF) but not placenta growth factor (PIGF). Further addition of VEGF resulted in cell dispersion, indicating the role of VEGF in the migration of ECs as well as their proliferation. Cell-cell adhesion of ECs in this culture system was mediated by VE-cadherin. Thus, the culture system described here is useful in dissecting the cellular events of EC progenitors that occur during vasculogenesis and in investigating the molecular mechanisms underlying these processes.

scholarly journals Identification and Characterization of Regulator of G Protein Signaling 4 (RGS4) as a Novel Inhibitor of Tubulogenesis: RGS4 Inhibits Mitogen-activated Protein Kinases and Vascular Endothelial Growth Factor Signaling

2005 ◽  
Vol 16 (2) ◽  
pp. 609-625 ◽  
Author(s):  
Allan R. Albig ◽  
William P. Schiemann
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
G Protein ◽  
P38 Mapk ◽  
G Protein Signaling ◽  
Vascular Endothelial ◽  
Protein Signaling ◽  
Mapk Activation ◽  
Endothelial Growth Factor

Tubulogenesis by epithelial cells regulates kidney, lung, and mammary development, whereas that by endothelial cells regulates vascular development. Although functionally dissimilar, the processes necessary for tubulation by epithelial and endothelial cells are very similar. We performed microarray analysis to further our understanding of tubulogenesis and observed a robust induction of regulator of G protein signaling 4 (RGS4) mRNA expression solely in tubulating cells, thereby implicating RGS4 as a potential regulator of tubulogenesis. Accordingly, RGS4 overexpression delayed and altered lung epithelial cell tubulation by selectively inhibiting G protein-mediated p38 MAPK activation, and, consequently, by reducing epithelial cell proliferation, migration, and expression of vascular endothelial growth factor (VEGF). The tubulogenic defects imparted by RGS4 in epithelial cells, including its reduction in VEGF expression, were rescued by overexpression of constitutively active MKK6, an activator of p38 MAPK. Similarly, RGS4 overexpression abrogated endothelial cell angiogenic sprouting by inhibiting their synthesis of DNA and invasion through synthetic basement membranes. We further show that RGS4 expression antagonized VEGF stimulation of DNA synthesis and extracellular signal-regulated kinase (ERK)1/ERK2 and p38 MAPK activation as well as ERK1/ERK2 activation stimulated by endothelin-1 and angiotensin II. RGS4 had no effect on the phosphorylation of Smad1 and Smad2 by bone morphogenic protein-7 and transforming growth factor-β, respectively, indicating that RGS4 selectively inhibits G protein and VEGF signaling in endothelial cells. Finally, we found that RGS4 reduced endothelial cell response to VEGF by decreasing VEGF receptor-2 (KDR) expression. We therefore propose RGS4 as a novel antagonist of epithelial and endothelial cell tubulogenesis that selectively antagonizes intracellular signaling by G proteins and VEGF, thereby inhibiting cell proliferation, migration, and invasion, and VEGF and KDR expression.

Abstract 555: Bone Morphogenetic Protein Modulator BMPER Induces Angiogenesis via Inhibition of Thrombospondin-1 and Activation of the Fibroblast Growth Factor Signaling Pathway

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Jennifer S Esser ◽  
Susanne Rahner ◽  
Meike Deckler ◽  
Christoph Bode ◽  
Martin Moser
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Cell Activity ◽  
Dependent Manner ◽  
Fgf Signaling ◽  
Endothelial Cell Function ◽  
Angiogenic Activity ◽  
Thrombospondin 1

Introduction: Bone morphogenetic proteins (BMP) play a key role in vascular development. Previously, we have identified BMP endothelial cell precursor-derived regulator (BMPER), an extracellular BMP modulator, to increase the angiogenic activity of endothelial cells in a concentration-dependent manner. In this project we now investigate how the BMPER effect is mediated by key molecules of angiogenesis. Methods and Results: To assess the effect of BMPER on angiogenesis-related molecules we performed an angiogenesis antibody array with BMPER-stimulated human umbilical venous endothelial cells (HUVECs) and vice versa with BMPER-silenced HUVECs compared to control conditions, respectively. We detected increased protein expression of the anti-angiogenic thrombospondin-1 (TSP-1) 48 hours after siBMPER transfection and, consistently, decreased TSP-1 expression after stimulation with BMPER (60 ng/ml; 39% ± 7.3 N=4). Furthermore, the pro-angiogenic protein bFGF was increased after BMPER stimulation, which was confirmed by realtime-PCR and western blot analysis (288.8% ± 74.8 N=3). Additionally, we detected increased FGF receptor-1 protein expression (137.7% ± 0.4 N=3) as well as FGF signaling pathway activation. Next, we investigated the interaction of BMPER and the FGF signaling pathway in endothelial cell function. BMPER stimulation increased HUVEC angiogenic activity in matrigel, migration and spheroid assays and concomitant inhibition of FGF signaling by an anti-bFGF antibody effectively inhibited the pro-angiogenic BMPER effect. Silencing of BMPER decreased the expression of FGFR1 and, accordingly, stimulation of BMPER-silenced cells with bFGF showed decreased angiogenic endothelial cell activity (65%) compared to control. The angiogenic activity of bFGF was also reduced in C57BL/6_Bmper +/- mice as assessed in the matrigel plug assay. Ex vivo aortic ring assays of C57BL/6_Bmper +/- mice confirmed a specific effect for bFGF but not for VEGF. Conclusion: In summary, BMPER inhibits the expression of the anti-angiogenic TSP-1 and increased the expression as well as activation of the pro-angiogenic FGF signaling pathway, which overall lead to the promotion of angiogenesis.

scholarly journals Andes Virus Disrupts the Endothelial Cell Barrier by Induction of Vascular Endothelial Growth Factor and Downregulation of VE-Cadherin

2010 ◽  
Vol 84 (21) ◽  
pp. 11227-11234 ◽  
Author(s):  
Punya Shrivastava-Ranjan ◽  
Pierre E. Rollin ◽  
Christina F. Spiropoulou
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Virus Replication ◽  
Cell Permeability ◽  
Hantavirus Infection ◽  
Vascular Endothelial ◽  
Andes Virus ◽  
Endothelial Growth Factor

ABSTRACT Hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS) are severe diseases associated with hantavirus infection. High levels of virus replication occur in microvascular endothelial cells but without a virus-induced cytopathic effect. However, virus infection results in microvascular leakage, which is the hallmark of these diseases. VE-cadherin is a major component of adherens junctions, and its interaction with the vascular endothelial growth factor (VEGF) receptor, VEGF-R2, is important for maintaining the integrity of the endothelial barrier. Here we report that increased secreted VEGF and concomitant decreased VE-cadherin are seen at early times postinfection of human primary lung endothelial cells with an HPS-associated hantavirus, Andes virus. Furthermore, active virus replication results in increased permeability and loss of the integrity of the endothelial cell barrier. VEGF binding to VEGF-R2 is known to result in dissociation of VEGF-R2 from VE-cadherin and in VE-cadherin activation, internalization, and degradation. Consistent with this, we showed that an antibody which blocks VEGF-R2 activation resulted in inhibition of the Andes virus-induced VE-cadherin reduction. These data implicate virus induction of VEGF and reduction in VE-cadherin in the endothelial cell permeability seen in HPS and suggest potential immunotherapeutic targets for the treatment of the disease.

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

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 1979-1987 ◽  
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.

Eicosanoid regulation of angiogenesis: role of endothelial arachidonate 12-lipoxygenase

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2304-2311
Author(s):  
Daotai Nie ◽  
Keqin Tang ◽  
Clement Diglio ◽  
Kenneth V. Honn
Keyword(s):  
Endothelial Cells ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Cell Line ◽  
Critical Role ◽  
Endothelial Cell Migration ◽  
Vascular Endothelial ◽  
12 Lipoxygenase

Angiogenesis, the formation of new capillaries from preexisting blood vessels, is a multistep, highly orchestrated process involving vessel sprouting, endothelial cell migration, proliferation, tube differentiation, and survival. Eicosanoids, arachidonic acid (AA)-derived metabolites, have potent biologic activities on vascular endothelial cells. Endothelial cells can synthesize various eicosanoids, including the 12-lipoxygenase (LOX) product 12(S)-hydroxyeicosatetraenoic acid (HETE). Here we demonstrate that endogenous 12-LOX is involved in endothelial cell angiogenic responses. First, the 12-LOX inhibitor, N-benzyl-N-hydroxy-5-phenylpentanamide (BHPP), reduced endothelial cell proliferation stimulated either by basic fibroblast growth factor (bFGF) or by vascular endothelial growth factor (VEGF). Second, 12-LOX inhibitors blocked VEGF-induced endothelial cell migration, and this blockage could be partially reversed by the addition of 12(S)-HETE. Third, pretreatment of an angiogenic endothelial cell line, RV-ECT, with BHPP significantly inhibited the formation of tubelike/cordlike structures within Matrigel. Fourth, overexpression of 12-LOX in the CD4 endothelial cell line significantly stimulated cell migration and tube differentiation. In agreement with the critical role of 12-LOX in endothelial cell angiogenic responses in vitro, the 12-LOX inhibitor BHPP significantly reduced bFGF-induced angiogenesis in vivo using a Matrigel implantation bioassay. These findings demonstrate that AA metabolism in endothelial cells, especially the 12-LOX pathway, plays a critical role in angiogenesis.

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