β-Catenin Is Required for Endothelial Cyp1b1 Regulation Influencing Metabolic Barrier Function

Ziegler, Nicole; Awwad, Khader; Fißlthaler, Beate; Reis, Marco; Devraj, Kavi; Corada, Monica; Minardi, Simone; Dejana, Elisabetta; Plate, Karl H.; Fleming, Ingrid; Liebner, Stefan

doi:10.1523/jneurosci.0148-16.2016

Cited by 35 publications

(36 citation statements)

References 51 publications

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“…cyp1b1 was shown to be one of the most highly expressed CYP enzymes in human brain microvessels from patient biopsies [ 43 ]. More recently it was shown that B-catenin positively regulates cyp1b1 , but not cyp1a1 , in endothelioma cell lines [ 44 ], and the authors concluded that the ability of cyp1b1 to synthesize retinoic acid (from retinol) and 20-HETE (from arachnidonic acid) were essential in modulating BBB function. Furthermore, this study demonstrated that B-catenin was required for the AHR-dependent induction of cyp1b1 expression by TCDD.…”

Section: Discussionmentioning

confidence: 99%

Genetic dissection of endothelial transcriptional activity of zebrafish aryl hydrocarbon receptors (AHRs)

et al. 2017

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The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix transcription factor conserved across phyla from flies to humans. Activated by a number of endogenous ligands and environmental toxins, studies on AHR function and gene regulation have largely focused on a toxicological perspective relating to aromatic hydrocarbons generated by human activities and the often-deleterious effects of exposure on vertebrates mediated by AHR activation. A growing body of work has highlighted the importance of AHR in physiologic processes, including immune cell differentiation and vascular patterning. Here we dissect the contribution of the 3 zebrafish AHRs, ahr1a, ahr1b and ahr2, to endothelial cyp1a1/b1 gene regulation under physiologic conditions and upon exposure to the AHR ligand Beta-naphthoflavone. We show that in fish multiple AHRs are functional in the vasculature, with vessel-specific differences in the ability of ahr1b to compensate for the loss of ahr2 to maintain AHR signaling. We further provide evidence that AHR can regulate the expression of the chemokine receptor cxcr4a in endothelial cells, a regulatory mechanism that may provide insight into AHR function in the endothelium.

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Section: Discussionmentioning

confidence: 99%

Genetic dissection of endothelial transcriptional activity of zebrafish aryl hydrocarbon receptors (AHRs)

et al. 2017

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“…We recently found that differentiating hPSC‐derived BMECs respond to all‐trans retinoic acid (RA), a hormone implicated in CNS development and hindbrain patterning and BBB development. Previous studies have identified RA production by astrocyte progenitor cells during embryonic BBB development and coordination with WNT signaling to promote BBB fidelity . During hPSC differentiation to BMECs, administration of RA during the EC expansion phase (D6–D8) and the first 24 h of the subculture phase (D8–D9) induced VE‐cadherin expression at D8, and the resulting BMECs exhibited dramatically elevated transendothelial electrical resistance (TEER) at D10 of the differentiation, an indicator of BMEC barrier function .…”

Section: Introductionmentioning

confidence: 99%

Activation of RARα, RARγ, or RXRα Increases Barrier Tightness in Human Induced Pluripotent Stem Cell‐Derived Brain Endothelial Cells

Stebbins

Lippmann

Faubion

et al. 2017

Biotechnology Journal

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The blood-brain barrier (BBB) is critical to central nervous system (CNS) health. Brain microvascular endothelial cells (BMECs) are often used as in vitro BBB models for studying BBB dysfunction and therapeutic screening applications. Human pluripotent stem cells (hPSCs) can be differentiated to cells having key BMEC barrier and transporter properties, offering a renewable, scalable source of human BMECs. hPSC-derived BMECs have previously been shown to respond to all-trans retinoic acid (RA), and the goal of this study was to identify the stages at which differentiating human induced pluripotent stem cells (iPSCs) respond to activation of RA receptors (RARs) to impart BBB phenotypes. Here the authors identified that RA application to iPSC-derived BMECs at days 6-8 of differentiation led to a substantial elevation in transendothelial electrical resistance and induction of VE-cadherin expression. Specific RAR agonists identified RARα, RARγ, and RXRα as receptors capable of inducing barrier phenotypes. Moreover, RAR/RXRα costimulation elevated VE-cadherin expression and improved barrier fidelity to levels that recapitulated the effects of RA. This study elucidates the roles of RA signaling in iPSC-derived BMEC differentiation, and identifies directed agonist approaches that can improve BMEC fidelity for drug screening studies while also distinguishing potential nuclear receptor targets to explore in BBB dysfunction and therapy.

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“…Treatment of ECs with the permeability-inducing factor thrombin induced the translocation of p120-catenin and β-catenin into the nucleus and the expression of β-catenin target genes, which indicated that the binding of p120-catenin and β-catenin to the AJ complex may reduce the signaling pathways of these molecules. Multiple studies suggest the role of β-cateninmediated Wnt transcription in EC biology and vascular development [39,40]. We demonstrate that β-catenin plays an important role in maintaining endothelial homeostasis.…”

Section: Discussionmentioning

confidence: 63%

hnRNPA2/B1 Ameliorates LPS-Induced Endothelial Injury through NF-κB Pathway and VE-Cadherin/β-Catenin Signaling Modulation In Vitro

Chen

Tang

Zhu

et al. 2020

Mediators of Inflammation

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Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) is a protein involved in the regulation of RNA processing, cell metabolism, migration, proliferation, and apoptosis. However, the effect of hnRNPA2/B1 on injured endothelial cells (ECs) remains unclear. We investigated the effect of hnRNPA2/B1 on lipopolysaccharide- (LPS-) induced vascular endothelial injury in human umbilical vein endothelial cells (HUVECs) and the underlying mechanisms. LPS was used to induce EC injury, and the roles of hnRNPA2/B1 in EC barrier dysfunction and inflammatory responses were measured by testing endothelial permeability and the expression of inflammatory factors after the suppression and overexpression of hnRNPA2/B1. To explore the underlying mechanism by which hnRNPA2/B1 regulates endothelial injury, we studied the VE-cadherin/β-catenin pathway and NF-κB activation in HUVECs. The results showed that hnRNPA2/B1 was elevated in LPS-stimulated HUVECs. Moreover, knockdown of hnRNPA2/B1 aggravated endothelial injury by increasing EC permeability and promoting the secretion of the inflammatory cytokines TNF-α, IL-1β, and IL-6. Overexpression of hnRNPA2/B1 can reduce the permeability and inflammatory response of HUVEC stimulated by LPS in vitro, while increasing the expression of VE-Cadherin and β-catenin. Furthermore, the suppression of hnRNPA2/B1 increased the LPS-induced NF-κB activation and reduced the VE-cadherin/β-catenin pathway. Taken together, these results suggest that hnRNPA2/B1 can regulate LPS-induced EC damage through regulating the NF-κB and VE-cadherin/β-catenin pathways.

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β-Catenin Is Required for Endothelial Cyp1b1 Regulation Influencing Metabolic Barrier Function

Cited by 35 publications

References 51 publications

Genetic dissection of endothelial transcriptional activity of zebrafish aryl hydrocarbon receptors (AHRs)

Genetic dissection of endothelial transcriptional activity of zebrafish aryl hydrocarbon receptors (AHRs)

Activation of RARα, RARγ, or RXRα Increases Barrier Tightness in Human Induced Pluripotent Stem Cell‐Derived Brain Endothelial Cells

hnRNPA2/B1 Ameliorates LPS-Induced Endothelial Injury through NF-κB Pathway and VE-Cadherin/β-Catenin Signaling Modulation In Vitro

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