Interleukin-1 increases tumor cell adhesion to endothelial cells through an RGD dependent mechanism: in vitro and in vivo studies

Abstract Introduction: Lipopolysaccharide (LPS) is one of the critical factors which induce endothelial inflammation during the pathogenesis of atherosclerosis, endocarditis and sepsis shock induced heart injury. The secretory Slit2 protein and its endothelial receptors Robo1 and Robo4 have been shown to regulate mobility and permeability of endothelial cells, which could be functional in regulating LPS induced endothelial inflammation. Hypothesis: We hypothesized that in addition to regulating permeability and migration of endothelial cells, Slit2-Robo1/4 signaling might regulate other LPS-induced endothelial inflammatory responses. Methods and Results: Using Human Umbilical Vein Endothelial Cells (HUVEC) culture, we observed that Slit2 treatment suppressed LPS-induced secretion of pro-inflammatory cytokines (including GM-CSF), cell adhesion molecule upregulation and monocyte (THP-1 cell) adhesion. With siRNA knock down techniques, we further confirmed that this anti-inflammatory effect is mediated by the interaction of Slit2 with its dominant receptor in endothelial cells, Robo4, though the much lesser expressed minor receptor Robo1 is pro-inflammatory. Our signaling studies showed that downstream of Robo4, Slit2 suppressed inflammatory gene expression by inhibiting the Pyk2 - NF-kB pathway following LPS-TLR4 interaction. In addition, Slit2 can induce a positive feedback to its expression and downregulate the pro-inflammatory Robo1 receptor via mediation of miR-218. Moreover, both in in vitro studies using HUVEC and in vivo mouse model studies indicated that LPS also causes endothelial inflammation by downregulating the anti-inflammatory Slit2 and Robo4 and upregulating the pro-inflammatory Robo1 during endotoxemia, especially in mouse arterial endothelial cells and whole heart. Conclusions: Slit2-Robo1/4 signaling is important in regulation of LPS induced endothelial inflammation, and LPS in turn causes inflammation by interfering with the expression of Slit2, Robo1 and Robo4. This implies that Slit2-Robo1/4 is a key regulator of endothelial inflammation and its dysregulation during endotoxemia is a novel mechanism for LPS induced cardiovascular pathogenesis.

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Chrysin Suppresses Vascular Endothelial Inflammation via Inhibiting the NF-κB Signaling Pathway

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248418810809 ◽

2018 ◽

Vol 24 (3) ◽

pp. 278-287 ◽

Cited By ~ 4

Author(s):

Shengnan Zhao ◽

Minglu Liang ◽

Yilong Wang ◽

Ji Hu ◽

Yi Zhong ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Adhesion ◽

Signaling Pathway ◽

Adhesion Molecule ◽

Intercellular Adhesion Molecule ◽

Flavonoid Compound ◽

Endothelial Inflammation ◽

Wide Range

The vascular endothelium is a continuous layer of flat polygonal cells that are in direct contact with the blood and participate in responses to inflammation. Chrysin is a flavonoid compound extracted from plants of the genus Asteraceae with a wide range of pharmacological activities and physiological activities. Here, we studied the effects of chrysin on the regulation of the proadhesion and pro-inflammatory phenotypes of the endothelium both in vitro and in vivo. Our results revealed that chrysin strongly inhibited Tohoku Hospital Pediatrics-1 (THP-1) cell adhesion to primary human umbilical vein endothelial cells and concentration-dependently attenuated interleukin 1β-induced increases in intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin messenger RNA levels and ICAM-1 and VCAM-1 protein levels. Previous studies reported that nuclear factor κB (NF-κB) is important in the inflammatory response in endothelial cells, particularly in regulating adhesion molecules, and our data shed light on the mechanisms whereby chrysin suppressed endothelial inflammation via the NF-κB signaling pathway. In addition, our in vivo findings demonstrated the effects of chrysin in the permeability and inflammatory responses of the endothelium to inflammatory injury. Taken together, we conclude that chrysin inhibits endothelial inflammation both in vitro and in vivo, which could be mainly due to its inhibition of NF-κB signaling activation. In conclusion, chrysin may serve as a promising therapeutic candidate for inflammatory vascular diseases.

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Ultrastructural localization of E-cadherin cell adhesion molecule on the cytoplasmic membrane of keratinocytes in vivo and in vitro.

Journal of Histochemistry & Cytochemistry ◽

10.1177/42.10.7930515 ◽

1994 ◽

Vol 42 (10) ◽

pp. 1333-1340 ◽

Cited By ~ 25

Author(s):

Y Horiguchi ◽

F Furukawa ◽

M Fujita ◽

S Imamura

Keyword(s):

Cell Adhesion ◽

Free Surface ◽

Adhesion Molecules ◽

Cell Adhesion Molecules ◽

Cytoplasmic Membrane ◽

Ultrastructural Localization ◽

In Vivo Studies ◽

E Cadherin

We examined the ultrastructural localization of E (epithelial)-cadherin cell adhesion molecules by immunoperoxidase electron microscopy on the epithelium of mouse intestine, epidermis of human skin, and cultured human keratinocytes. The in vivo studies demonstrated that E-cadherin was present at the intermediate junction but not at the desmosome of the mouse intestinal single epithelium, and was found on the cytoplasmic membranes of keratinocytes with condensation in the intercellular space of the desmosomes, except for the basal surface of the basal cells. In vitro studies demonstrated that keratinocytes cultured in medium containing a low Ca2+ concentration (0.1 mM) lacked the tight connection through desmosomes, and that E-cadherin showed diffuse distribution and dot-like accumulation around the free surface of the cytoplasmic membrane. In culture medium containing a high concentration of Ca2+ (0.6 mM), keratinocytes formed desmosomal adhesion structures in which E-cadherin was accumulated. The free surface of the keratinocytes in this medium showed weaker distribution and a lesser amount of dot-like accumulation of E-cadherin than that in a low Ca2+ condition. These findings suggest that the distribution pattern of the E-cadherin cell adhesion molecules on the keratinocytes is different from that on the single epithelium of the intestine, and that E-cadherin on the cytoplasmic membrane of the keratinocytes shifts to the desmosomes under physiological conditions, participating in adhesion in association with other desmosomal cadherins.

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The vacuolar-type ATPase inhibitor archazolid increases tumor cell adhesion to endothelial cells by accumulating extracellular collagen

PLoS ONE ◽

10.1371/journal.pone.0203053 ◽

2018 ◽

Vol 13 (9) ◽

pp. e0203053 ◽

Cited By ~ 2

Author(s):

Betty Luong ◽

Rebecca Schwenk ◽

Jacqueline Bräutigam ◽

Rolf Müller ◽

Dirk Menche ◽

...

Keyword(s):

Endothelial Cells ◽

Cell Adhesion ◽

Tumor Cell ◽

Atpase Inhibitor ◽

Tumor Cell Adhesion

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Factor VIIa induces extracellular vesicles from the endothelium: A potential mechanism for its hemostatic effect

Blood ◽

10.1182/blood.2020008417 ◽

2021 ◽

Author(s):

Kaushik Das ◽

Shiva Keshava ◽

Shabbir A Ansari ◽

Vijay Kumar Reddy Kondreddy ◽

Charles Esmon ◽

...

Keyword(s):

Endothelial Cells ◽

Extracellular Vesicles ◽

Factor Viia ◽

Mutant Mice ◽

In Vivo Studies ◽

Cell Protein ◽

Wild Type ◽

Hemostatic Effect

Recombinant FVIIa (rFVIIa) is used as a hemostatic agent to treat bleeding disorders in hemophilia patients with inhibitors and other groups of patients. Our recent studies showed that FVIIa binds endothelial cell protein C receptor (EPCR) and induces protease-activated receptor 1 (PAR1)-mediated biased signaling. The importance of FVIIa-EPCR-PAR1-mediated signaling in hemostasis is unknown. In the present study, we show that FVIIa induces the release of extracellular vesicles (EVs) from endothelial cells both in vitro and in vivo. Silencing of EPCR or PAR1 in endothelial cells blocked the FVIIa-induced generation of EVs. Consistent with these data, FVIIa treatment enhanced the release of EVs from murine brain endothelial cells isolated from wild-type, EPCR overexpressors, and PAR1-R46Q mutant mice, but not EPCR-deficient or PAR1-R41Q mutant mice. In vivo studies revealed that administration of FVIIa to wild-type, EPCR overexpressors, and PAR1-R46Q mutant mice, but not EPCR-deficient or PAR1-R41Q mutant mice, increase the number of circulating EVs. EVs released in response to FVIIa treatment exhibit enhanced procoagulant activity. Infusion of FVIIa-generated EVs and not control EVs to platelet-depleted mice increased thrombin generation at the site of injury and reduced blood loss. Administration of FVIIa-generated EVs or generation of EVs endogenously by administering FVIIa augmented the hemostatic effect of FVIIa. Overall, our data reveal that FVIIa treatment, through FVIIa-EPCR-PAR1 signaling, releases EVs from the endothelium into the circulation, and these EVs contribute to the hemostatic effect of FVIIa.

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Cardioprotective Activity of Selected Polyphenols Based on Epithelial and Aortic Cell Lines. A Review

Molecules ◽

10.3390/molecules25225343 ◽

2020 ◽

Vol 25 (22) ◽

pp. 5343

Author(s):

Michał Otręba ◽

Leon Kośmider ◽

Jerzy Stojko ◽

Anna Rzepecka-Stojko

Keyword(s):

Endothelial Cells ◽

Tube Formation ◽

Health Claims ◽

In Vivo Studies ◽

Positive Effects ◽

Endothelial Tube Formation ◽

Disease Therapy ◽

Species Production

Polyphenols have recently gained popularity among the general public as products and diets classified as healthy and containing naturally occurring phenols. Many polyphenolic extracts are available on the market as dietary supplements, functional foods, or cosmetics, taking advantage of clients’ desire to live a healthier and longer life. However, due to the difficulty of discovering the in vivo functions of polyphenols, most of the research focuses on in vitro studies. In this review, we focused on the cardioprotective activity of different polyphenols as possible candidates for use in cardiovascular disease therapy and for improving the quality of life of patients. Thus, the studies, which were mainly based on endothelial cells, aortic cells, and some in vivo studies, were analyzed. Based on the reviewed articles, polyphenols have a few points of action, including inhibition of acetylcholinesterase, decrease in reactive oxygen species production and endothelial tube formation, stimulation of acetylcholine-induced endothelium-derived mediator release, and others, which lead to their cardio- and/or vasoprotective effects on endothelial cells. The obtained results suggest positive effects of polyphenols, but more long-term in vivo studies demonstrating effects on mechanism of action, sensitivity, and specificity or efficacy are needed before legal health claims can be made.

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