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Wnt5A signaling in human coronary artery endothelial cells

ABSTRACT: Inflammatory Wnt5A signalling in human macrophages was found to be critically involved in severe systemic inflammatory response. However, the targets of Wnt5A in endothelial cells and downstream mechanisms by which Wnt5A might induce endothelial inflammation still remain unclear. We show that Wnt5A principally regulate genes involved endothelial cytoskeleton rearrangements and impairs the barrier function of cultured endothelial monolayer causing hyper permeability. We further prove that Wnt5A neither affects the expression of adhesion molecules nor induces cytokine storm in endothelial cells. These findings suggest that Wnt5A, secreted by activated macrophages during septic inflammation, paracrinically act on the endothelial wall, causing endothelial barrier breakdown and subsequent vascular leakage in sepsis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE62281 | GEO | 2016/10/03

SECONDARY ACCESSION(S): PRJNA263656

REPOSITORIES: GEO

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Proinflammatory signaling mediated by the combined action of IL-1/Wnt5A in human coronary artery endothelial cells

Project description:IL-1b and Wnt5A are released from macrophages in systemic inflammation and sepsis. However, the early response targets for the paracrine action of synergistic interaction of IL-1b with Wnt5A in vascular endothelial cells still remain unclear. Here we show that IL-1b synergizes with Wnt5A to stimulate vascular endothelial inflammatory pathways involved in barrier dysfunction. Molecular targets involved in actin cytoskeleton remodeling, coagulation and stress signaling which are targets for known drugs are regulated by the synergistic action.

2021-06-09 | GSE146691 | GEO

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Project description:Wnt5A is released from macrophages during systemic inflammation and sepsis. However, the early response targets for the paracrine action of macrophage derived Wnt5A in vascular endothelial cells still remain unclear. Here we show that Wnt5A regulates the expression of distinct molecular targets involved in inflammation, coagulation and extracellular matrix remodeling. The proteins encoded by these genes are direct targets for known drugs. Regulation of these specific targets by Wnt5A can modulate the drug response and efficiency.

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IL-4 signaling in human coronary artery endothelial cells

Project description:IL-4 signalling is critically involved in Th2 driven allergic inflammatory responses. IL-4 generates a proinflammatory enviornment and may cause barrier dysfunction in vascular endothelial cells (VECs). However, the effectors responsible for IL-4 induced barrier dysfunction in adult human VECs still remain unclear. Here we show that IL-4 upregulates the expression of Wnt5A which can mediate cytoskeleton remodeling in VECs. We further show that IL-4 induced cytoskeleton remodeling involving stress fiber formation can be decreased by antagonizing Wnt5A. Further we demonstrate that silencing Wnt5A significantly improves the barrier function of IL-4 treated endothelial monolayer. Additionally, we rule out the involvement of IL-6 in IL-4 induced barrier dysfunction of VECs. These findings suggest a critical role for Wnt5A in mediating IL-4 induced endothelial barrier dysfunction and edem formation in Th2 driven inflammatory diseases.

2016-10-03 | GSE64860 | GEO

HIF2 regulates intestinal Wnt5a expression

Project description:Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs). Our group has previously shown that stabilization of HIF2 through genetic deletion or pharmacologic inhibition of the EGLNs mitigates and protects against GI radiotoxicity in mice by improving intestinal crypt stem cell survival. Here we aimed to elucidate the molecular mechanisms by which HIF2 confers GI radioprotection. We developed duodenal organoids from mice, transiently overexpressed non-degradable HIF2, and performed bulk RNA sequencing. Interestingly, HIF2 upregulated known radiation modulators and genes involved in GI homeostasis, including Wnt5a. Non-canonical Wnt5a signaling has been shown by other groups to improve intestinal crypt regeneration in response to injury. Here we show that HIF2 drives Wnt5a expression in multiple duodenal organoid models. Luciferase reporter assays performed in human cells showed that HIF2 directly activates the WNT5A promoter via a hypoxia response element. We then evaluated crypt regeneration using spheroid formation assays. Duodenal organoids that were pre-treated with recombinant Wnt5a had a higher cryptogenic capacity after irradiation, compared to vehicle-treated organoids. Conversely, we found that Wnt5a knockout decreased the cryptogenic potential of intestinal stem cells following irradiation. Treatment with recombinant Wnt5a prior to irradiation rescued the cryptogenic capacity of Wnt5a knockout organoids, indicating that Wnt5a is necessary and sufficient for duodenal radioprotection. Taken together, our results.txt suggest that HIF2 radioprotects the GI tract by inducing Wnt5a expression.

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Wnt5a-deficient vs. wild-type E18 liver

Project description:Transcriptional profiling of E18.5 livers derived from Wnt5a-deficient (KO) mice compared to those from littermate wild-type (WT) mice. RNA samples were extracted from whole livers derived from E18.5 fetuses. Two-condition experiment: Wnt5a KO vs. WT whole livers. Total RNA samples were extracted from E18.5 whole livers. KO and WT samples were a mixture of RNA solutions derived from two Wnt5a KO livers and two WT livers, respectively.

2013-02-07 | E-GEOD-41803 | biostudies-arrayexpress

Wnt5A Enhances Resistance of Melanoma Cells to Targeted BRAF Inhibitors

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2014-03-06 | E-GEOD-55583 | biostudies-arrayexpress

HIF2 regulates intestinal Wnt5a expression

Project description:HIF2 regulates intestinal Wnt5a expression

| PRJNA776829 | ENA

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Project description:Transcriptome profiling of Wnt5A activated human coronary artery endothelial cells

| PRJNA608921 | ENA

NTRAS hnRNPL RNA sequencing in HUVECs

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Wnt5A Enhances Resistance of Melanoma Cells to Targeted BRAF Inhibitors

2014-03-06 | GSE55583 | GEO

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