Dataset Information

Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling.

ABSTRACT: Endothelial cells respond to molecular and physical forces in development and vascular homeostasis. Deregulation of endothelial responses to flow-induced shear is believed to contribute to many aspects of cardiovascular diseases including atherosclerosis. However, how molecular signals and shear-mediated physical forces integrate to regulate vascular patterning is poorly understood. Here we show that endothelial non-canonical Wnt signalling regulates endothelial sensitivity to shear forces. Loss of Wnt5a/Wnt11 renders endothelial cells more sensitive to shear, resulting in axial polarization and migration against flow at lower shear levels. Integration of flow modelling and polarity analysis in entire vascular networks demonstrates that polarization against flow is achieved differentially in artery, vein, capillaries and the primitive sprouting front. Collectively our data suggest that non-canonical Wnt signalling stabilizes forming vascular networks by reducing endothelial shear sensitivity, thus keeping vessels open under low flow conditions that prevail in the primitive plexus.

SUBMITTER: Franco CA

PROVIDER: S-EPMC4798962 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling.

Franco Claudio A CA Jones Martin L ML Bernabeu Miguel O MO Vion Anne-Clemence AC Barbacena Pedro P Fan Jieqing J Mathivet Thomas T Fonseca Catarina G CG Ragab Anan A Yamaguchi Terry P TP Coveney Peter V PV Lang Richard A RA Gerhardt Holger H

eLife 20160204

Endothelial cells respond to molecular and physical forces in development and vascular homeostasis. Deregulation of endothelial responses to flow-induced shear is believed to contribute to many aspects of cardiovascular diseases including atherosclerosis. However, how molecular signals and shear-mediated physical forces integrate to regulate vascular patterning is poorly understood. Here we show that endothelial non-canonical Wnt signalling regulates endothelial sensitivity to shear forces. Loss ...[more]

PMID: 26845523

Similar Datasets

Project description:ObjectiveReactive oxygen species regulate canonical Wnt signaling. However, the role of the redox regulatory protein p66(Shc) in the canonical Wnt pathway is not known. We investigated whether p66(Shc) is essential for canonical Wnt signaling in the endothelium and determined whether the canonical Wnt pathway induces vascular endothelial dysfunction via p66(Shc)-mediated oxidative stress.Approach and resultsThe canonical Wnt ligand Wnt3a induced phosphorylation (activation) of p66(Shc) in endothelial cells. Wnt3a-stimulated dephosphorylation of β-catenin, and β-catenin-dependent transcription, was inhibited by knockdown of p66(Shc). Exogenous H2O2-induced β-catenin dephosphorylation was also mediated by p66(Shc). Moreover, p66(Shc) overexpression dephosphorylated β-catenin and increased β-catenin-dependent transcription, independent of Wnt3a ligand. P66(Shc)-induced β-catenin dephosphorylation was inhibited by antioxidants N-acetyl cysteine and catalase. Wnt3a upregulated endothelial NADPH oxidase-4, and β-catenin dephosphorylation was suppressed by knocking down NADPH oxidase-4 and by antioxidants. Wnt3a increased H2O2 levels in endothelial cells and impaired endothelium-dependent vasorelaxation in mouse aortas, both of which were rescued by p66(Shc) knockdown. P66(Shc) knockdown also inhibited adhesion of monocytes to Wnt3a-stimulated endothelial cells. Furthermore, constitutively active β-catenin expression in the endothelium increased vascular reactive oxygen species and impaired endothelium-dependent vasorelaxation. In vivo, high-fat diet feeding-induced endothelial dysfunction in mice was associated with increased endothelial Wnt3a, dephosphorylated β-catenin, and phosphorylated p66(Shc). High-fat diet-induced dephosphorylation of endothelial β-catenin was diminished in mice in which p66(Shc) was knocked down.Conclusionsp66(Shc) plays a vital part in canonical Wnt signaling in the endothelium and mediates Wnt3a-stimulated endothelial oxidative stress and dysfunction.

Project description:Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic β-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.

Dataset Information

Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling.

Publications

Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets