Overlapping and divergent signaling pathways of N-cadherin and VE-cadherin in endothelial cells

Abstract Endothelial cells (ECs) express 2 members of the cadherin family, VE and N-cadherin. Although VE-cadherin induces EC homotypic adhesion, N-cadherin function in ECs remains largely unknown. EC-specific inactivation of either VE or N-cadherin leads to early fetal lethality suggesting that these cadherins play a nonredundant role in vascular development. We report here that VE-cadherin negatively controls junctional localization and expression of N-cadherin by limiting p120-catenin availability and reducing β-catenin transcriptional activity. Using EC lines expressing either VE or N-cadherin we found that both cadherins inhibit cell proliferation and apoptosis. Both trigger the phosphatidylinositol-3-OH-kinase (PI3K)–AKT-Forkhead-box protein-O1 (FoxO1) pathway and reduce β-catenin transcriptional activity. The extent of signaling correlates with the total level of cadherins regardless of the type of cadherin expressed. In contrast, basal and fibroblast growth factor (FGF)–induced cell motility is promoted by N-cadherin and strongly inhibited by VE-cadherin. This opposite effect is partly because of the ability of VE-cadherin to associate with FGF receptor and the density-enhanced phosphatase-1 (Dep-1) which, in turn, inhibits receptor signaling. We conclude that VE and N-cadherin have both additive and divergent effects on ECs. Differences in signaling are due, in part, to cadherin association with growth factor receptors and modulation of their downstream signaling.

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Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1

Scientific Reports ◽

10.1038/s41598-021-95511-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Samir Sissaoui ◽

Stuart Egginton ◽

Ling Ting ◽

Asif Ahmed ◽

Peter W. Hewett

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Endothelial Dysfunction ◽

Akt Activation ◽

Forkhead Box ◽

Pi3k Activity ◽

Binding Sequence

AbstractPlacenta growth factor (PlGF) is a pro-inflammatory angiogenic mediator that promotes many pathologies including diabetic complications and atherosclerosis. Widespread endothelial dysfunction precedes the onset of these conditions. As very little is known of the mechanism(s) controlling PlGF expression in pathology we investigated the role of hyperglycaemia in the regulation of PlGF production in endothelial cells. Hyperglycaemia stimulated PlGF secretion in cultured primary endothelial cells, which was suppressed by IGF-1-mediated PI3K/Akt activation. Inhibition of PI3K activity resulted in significant PlGF mRNA up-regulation and protein secretion. Similarly, loss or inhibition of Akt activity significantly increased basal PlGF expression and prevented any further PlGF secretion in hyperglycaemia. Conversely, constitutive Akt activation blocked PlGF secretion irrespective of upstream PI3K activity demonstrating that Akt is a central regulator of PlGF expression. Knock-down of the Forkhead box O-1 (FOXO1) transcription factor, which is negatively regulated by Akt, suppressed both basal and hyperglycaemia-induced PlGF secretion, whilst FOXO1 gain-of-function up-regulated PlGF in vitro and in vivo. FOXO1 association to a FOXO binding sequence identified in the PlGF promoter also increased in hyperglycaemia. This study identifies the PI3K/Akt/FOXO1 signalling axis as a key regulator of PlGF expression and unifying pathway by which PlGF may contribute to common disorders characterised by endothelial dysfunction, providing a target for therapy.

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Heterodimerization of FGF-receptor 1 and PDGF-receptor-α: a novel mechanism underlying the inhibitory effect of PDGF-BB on FGF-2 in human cells

Blood ◽

10.1182/blood-2005-04-1524 ◽

2006 ◽

Vol 107 (5) ◽

pp. 1896-1902 ◽

Cited By ~ 32

Author(s):

Debora Faraone ◽

Maria S. Aguzzi ◽

Gianluca Ragone ◽

Katia Russo ◽

Maurizio C. Capogrossi ◽

...

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Intracellular Signaling ◽

Cell Function ◽

Umbilical Vein ◽

Pdgf Receptor ◽

Inhibitory Effects ◽

Fgf Receptor ◽

Endothelial Cell Function

Previous evidence has shown that platelet-derived growth factor-BB (PDGF-BB) and fibroblast growth factor-2 (FGF-2) directly interact with high affinity, leading to potent reciprocal inhibitory effects on bovine endothelial cells and rat vascular smooth muscle cells. In this study, we report that PDGF-BB inhibits a series of FGF-2–induced events, such as proliferation of human umbilical vein endothelial cells (HUVECs), FGF-2 cellular internalization, phosphorylation of intracellular signaling factors including p38, rac1/cdc42, MKK4, and MKK3/6, and phosphorylation of FGF-receptor 1 (FGF-R1). PDGF-receptor-α (PDGF-Rα) was found to mediate PDGF-BB inhibitory effects because its neutralization fully restored FGF-2 mitogenic activity and internalization. Additional biochemical analyses, coimmunoprecipitation experiments, and FRET analysis showed that FGF-R1 and PDGF-Rα directly interact in vitro and in vivo and that this interaction is somehow increased in the presence of the corresponding ligands FGF-2 and PDGF-BB. These results suggest that FGF-R1/PDGF-Rα heterodimerization may represent a novel endogenous mechanism to modulate the action of these receptors and their ligands and to control endothelial cell function.

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Adherens junction protein, p120 catenin, represses transcriptional activity of endothelial cells

The FASEB Journal ◽

10.1096/fasebj.23.1_supplement.1028.3 ◽

2009 ◽

Vol 23 (S1) ◽

Author(s):

Hazel Lum ◽

Feng Cheng ◽

James J. O'Donnell ◽

Hee‐jeong Im ◽

Oksana Holian

Keyword(s):

Endothelial Cells ◽

Transcriptional Activity ◽

Adherens Junction ◽

P120 Catenin ◽

Adherens Junction Protein ◽

Junction Protein

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P120 catenin represses transcriptional activity through Kaiso in endothelial cells

Microvascular Research ◽

10.1016/j.mvr.2010.04.001 ◽

2010 ◽

Vol 80 (2) ◽

pp. 233-239 ◽

Cited By ~ 9

Author(s):

Jihang Zhang ◽

James J. O'Donnell ◽

Oksana Holian ◽

Peter A. Vincent ◽

Kwang S. Kim ◽

...

Keyword(s):

Endothelial Cells ◽

Transcriptional Activity ◽

P120 Catenin

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miR-17 regulates the proliferation and apoptosis of endothelial cells in coronary heart disease via targeting insulin-like-growth factor 1

Pathology - Research and Practice ◽

10.1016/j.prp.2019.152512 ◽

2019 ◽

Vol 215 (9) ◽

pp. 152512 ◽

Cited By ~ 4

Author(s):

Zhongpu Chen ◽

Xiaodong Pan ◽

Zulong Sheng ◽

Gaoliang Yan ◽

Long Chen ◽

...

Keyword(s):

Coronary Heart Disease ◽

Endothelial Cells ◽

Heart Disease ◽

Growth Factor ◽

Insulin Like Growth Factor ◽

Proliferation And Apoptosis

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Silencing of FOXG1 confers radio-sensitivity through regulating autophagy in glioma cells

10.21203/rs.2.17497/v1 ◽

2019 ◽

Author(s):

Wenjun Liao ◽

Churong Li ◽

Jun Yin ◽

Hui Huang ◽

Baisen Li ◽

...

Keyword(s):

Opposite Effect ◽

Glioma Cells ◽

Proliferation Inhibition ◽

X Ray ◽

Forkhead Box ◽

Proliferation And Apoptosis ◽

Radiation Induced ◽

Malignant Glioma Cells ◽

Radio Sensitivity ◽

Related Proteins

Abstract Background/Aim forkhead box G1 (FOXG1) has recently been observed in many cancers, while its effect on radio-sensitivity in glioma is still unclear. In this study, we hypothesized that FOXG1 be a major players in radio-resistance of glioma as well as the underlying mechanism.Methods Immunohistochemistry (IHC) was conducted to assess FOXG1 expression in the glioma tissues and glioma-adjacent tissues. Western Blot was applied to detect the expression of autophagy-related proteins. CCK-8 and flow cytometry assays were applied to assess proliferation and apoptosis, respectively.Results The present study demonstrated that FOXG1 was highly expressed in glioma tissues. FOXG1 silencing enhances the effect of X-ray irradiation on proliferation inhibition and apoptosis of glioma cells, while FOXG1 overexpression has the opposite effect. Interestingly, the chloroquine (CQ) of autophagy inhibitor enhanced X-ray irradiation induces proliferation inhibition and apoptosis in glioma cells.Conclusions The present study suggests that FOXG1 is a pivotal molecule for circumventing radiation-induced cell death in malignant glioma cells through the regulation of autophagy and provide a target for the treatment of human brain glioma.

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Isolation and characterization of human thyroid endothelial cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00096.2002 ◽

2003 ◽

Vol 284 (1) ◽

pp. E168-E176 ◽

Cited By ~ 21

Author(s):

Vimal A. Patel ◽

Ann Logan ◽

John C. Watkinson ◽

Saad Uz-Zaman ◽

Michael C. Sheppard ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Growth Factor ◽

Specific Inhibitor ◽

Growth Inhibitor ◽

Human Thyroid ◽

Follicular Cells ◽

Isolated Cells ◽

Fgf Receptor ◽

Isolation And Characterization

From collagenase digests of human thyroid, endothelial cells were separated from follicular cells by their greater adherence to gelatin-coated plates. Endothelial cells were further purified using fluorescence-activated cell sorting, selecting for cells expressing factor VIII-related antigen. Isolated cells were negative for thyroglobulin and calcitonin when examined by immunostaining. The receptor for the angiopoietins, Tie-2, was expressed by the cells, and expression was increased by agents that elevate cAMP. Nitric oxide synthase (NOS) 3, the endothelial form of NOS, was expressed by the cells and similarly regulated. Cells responded strongly to the mitogen fibroblast growth factor (FGF)-2 in growth assays but only weakly to vascular endothelial growth factor (VEGF). VEGF was, however, able to stimulate nitric oxide release from the cells consistent with their endothelial origin. The FGF receptor (FGFR1) was full length (120 kDa) and immunolocalized to the cytosol and nucleus. Thyrotropin (TSH) did not regulate FGFR1, but its expression was increased by VEGF. Thrombospondin, a product of follicular cells, was a growth inhibitor, but neither TSH nor 3,5,3′-triiodothyronine had direct mitogenic effects. Thyroid follicular cell conditioned medium contained plasminogen activator activity and stimulated the growth of the endothelial cells, but when treated with plasminogen to produce the endothelial-specific inhibitor, angiostatin, growth was inhibited. Human thyroid endothelial cell cultures will be invaluable in determining the cross talk between endothelial and follicular cells during goitrogenesis.

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