Regulation of endothelial nitric oxide synthase activation in endothelial cells by S1P1 and S1P3

Tölle, Markus; Klöckl, L; Wiedon, Annette; Zidek, Walter; Giet, Markus van der; Schuchardt, Mirjam

doi:10.1016/j.bbrc.2016.06.009

Cited by 18 publications

(9 citation statements)

References 41 publications

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“…Additional experiments confirmed the potency of L-NAME to block eNOS in HDL-stimulated HUVEC (Additional file 2 a), yet this also had no effect on the ability of HDL to suppress either Aβ- or TNF-α- mediated PBMC binding in HUVEC (Additional file 2 b–d). We further ruled out a role for the NO pathway in hCMEC/D3 by measuring the effect of HDL in the presence of VPC23019, an antagonist of sphingosine-1 phosphate receptor 1 (S1P1) and S1P3, receptors that are required for eNOS activity [ 26 ], and again found no effect on the ability of HDL to suppress either Aβ- or TNF-α-mediated PBMC adhesion to hCMEC/D3 (Fig. 4g-i ) or HUVEC (Additional file 2 e–h).…”

Section: Resultsmentioning

confidence: 99%

High-density lipoproteins suppress Aβ-induced PBMC adhesion to human endothelial cells in bioengineered vessels and in monoculture

Robert

Button

Stukas

et al. 2017

Mol Neurodegeneration

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BackgroundAlzheimer’s Disease (AD), characterized by accumulation of beta-amyloid (Aβ) plaques in the brain, can be caused by age-related failures to clear Aβ from the brain through pathways that involve the cerebrovasculature. Vascular risk factors are known to increase AD risk, but less is known about potential protective factors. We hypothesize that high-density lipoproteins (HDL) may protect against AD, as HDL have vasoprotective properties that are well described for peripheral vessels. Epidemiological studies suggest that HDL is associated with reduced AD risk, and animal model studies support a beneficial role for HDL in selectively reducing cerebrovascular amyloid deposition and neuroinflammation. However, the mechanism by which HDL may protect the cerebrovascular endothelium in the context of AD is not understood.MethodsWe used peripheral blood mononuclear cell adhesion assays in both a highly novel three dimensional (3D) biomimetic model of the human vasculature composed of primary human endothelial cells (EC) and smooth muscle cells cultured under flow conditions, as well as in monolayer cultures of ECs, to study how HDL protects ECs from the detrimental effects of Aβ.ResultsFollowing Aβ addition to the abluminal (brain) side of the vessel, we demonstrate that HDL circulated within the lumen attenuates monocyte adhesion to ECs in this biofidelic vascular model. The mechanism by which HDL suppresses Aβ-mediated monocyte adhesion to ECs was investigated using monotypic EC cultures. We show that HDL reduces Aβ-induced PBMC adhesion to ECs independent of nitric oxide (NO) production, miR-233 and changes in adhesion molecule expression. Rather, HDL acts through scavenger receptor (SR)-BI to block Aβ uptake into ECs and, in cell-free assays, can maintain Aβ in a soluble state. We confirm the role of SR-BI in our bioengineered human vessel.ConclusionOur results define a novel activity of HDL that suppresses Aβ-mediated monocyte adhesion to the cerebrovascular endothelium.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0201-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

High-density lipoproteins suppress Aβ-induced PBMC adhesion to human endothelial cells in bioengineered vessels and in monoculture

Robert

Button

Stukas

et al. 2017

Mol Neurodegeneration

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“…Recent work of Tölle and co-workers demonstrated that S1P plays a role in activation of human eNOS since both S1PR1 and S1PR3 were essential for eNOS activation in human endothelial HUVEC cells38. However, results from clinical studies on Fingolimod show that agonism of S1P receptors transiently lowers heart rate and SBP while a chronic treatment may increase SBP by 1–3 mmHg39.…”

Section: Discussionmentioning

confidence: 99%

Vascular transcriptome profiling identifies Sphingosine kinase 1 as a modulator of angiotensin II-induced vascular dysfunction

Siedliński

Nosalski

Szczepaniak

et al. 2017

Sci Rep

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Vascular dysfunction is an important phenomenon in hypertension. We hypothesized that angiotensin II (AngII) affects transcriptome in the vasculature in a region-specific manner, which may help to identify genes related to vascular dysfunction in AngII-induced hypertension. Mesenteric artery and aortic transcriptome was profiled using Illumina WG-6v2.0 chip in control and AngII infused (490 ng/kg/min) hypertensive mice. Gene set enrichment and leading edge analyses identified Sphingosine kinase 1 (Sphk1) in the highest number of pathways affected by AngII. Sphk1 mRNA, protein and activity were up-regulated in the hypertensive vasculature. Chronic sphingosine-1-phosphate (S1P) infusion resulted in a development of significantly increased vasoconstriction and endothelial dysfunction. AngII-induced hypertension was blunted in Sphk1−/− mice (systolic BP 167 ± 4.2 vs. 180 ± 3.3 mmHg, p < 0.05), which was associated with decreased aortic and mesenteric vasoconstriction in hypertensive Sphk1−/− mice. Pharmacological inhibition of S1P synthesis reduced vasoconstriction of mesenteric arteries. While Sphk1 is important in mediating vasoconstriction in hypertension, Sphk1−/− mice were characterized by enhanced endothelial dysfunction, suggesting a local protective role of Sphk1 in the endothelium. S1P serum level in humans was correlated with endothelial function (arterial tonometry). Thus, vascular transcriptome analysis shows that S1P pathway is critical in the regulation of vascular function in AngII-induced hypertension, although Sphk1 may have opposing roles in the regulation of vasoconstriction and endothelium-dependent vasorelaxation.

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“…S1P 1 responds to laminar shear stress to confer flow-dependent signaling in endothelial cells both in vitro and in vivo, and which stabilizes blood vessel development and homeostasis [40]. Significantly, S1P also exerts a protective role in endothelial cells by binding to S1P 1/3 receptors to promote eNOS signaling [35].…”

Section: Sphk1 and Endothelial Cell Functionmentioning

confidence: 99%

Sphingosine Kinase 1: A Potential Therapeutic Target in Pulmonary Arterial Hypertension?

Pyne

2017

Trends in Molecular Medicine

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This version is available at https://strathprints.strath.ac.uk/61649/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Strathprints administrator: strathprints@strath.ac.ukThe Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output. Abstract--Sphingosine kinase 1 (SphK1) knockout mice are protected against pulmonary hypertension and expression levels of the enzyme are increased in the lungs of pulmonary arterial hypertensive (PAH) patients. Moreover, sphingosine 1-phosphate can promote vascular remodeling/vasoconstriction in rodent and human pulmonary arterial smooth muscle cell models. Therefore, SphK1 might be a novel target for treatment of PAH.

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Regulation of endothelial nitric oxide synthase activation in endothelial cells by S1P1 and S1P3

Cited by 18 publications

References 41 publications

High-density lipoproteins suppress Aβ-induced PBMC adhesion to human endothelial cells in bioengineered vessels and in monoculture

High-density lipoproteins suppress Aβ-induced PBMC adhesion to human endothelial cells in bioengineered vessels and in monoculture

Vascular transcriptome profiling identifies Sphingosine kinase 1 as a modulator of angiotensin II-induced vascular dysfunction

Sphingosine Kinase 1: A Potential Therapeutic Target in Pulmonary Arterial Hypertension?

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