Wnt7a Decreases Brain Endothelial Barrier Function Via β-Catenin Activation

Narek Manukjan, Steven Chau, Florian Caiment, Marcel van Herwijnen, Hubert J. Smeets, Daniel Fulton, Zubair Ahmed*, W. Matthijs Blankesteijn, Sébastien Foulquier

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Downloads (Pure)

Abstract

The blood-brain barrier consists of tightly connected endothelial cells protecting the brain’s microenvironment from the periphery. These endothelial cells are characterized by specific tight junction proteins such as Claudin-5 and Occludin, forming the endothelial barrier. Disrupting these cells might lead to blood-brain barrier dysfunction. The Wnt/β-catenin signaling pathway can regulate the expression of these tight junction proteins and subsequent barrier permeability. The aim of this study was to investigate the in vitro effects of Wnt7a mediated β-catenin signaling on endothelial barrier integrity. Mouse brain endothelial cells, bEnd.3, were treated with recombinant Wnt7a protein or XAV939, a selective inhibitor of Wnt/β-catenin mediated transcription to modulate the Wnt signaling pathway. The involvement of Wnt/HIF1α signaling was investigated by inhibiting Hif1α signaling with Hif1α siRNA. Wnt7a stimulation led to activation and nuclear translocation of β-catenin, which was inhibited by XAV939. Wnt7a stimulation decreased Claudin-5 expression mediated by β-catenin and decreased endothelial barrier formation. Wnt7a increased Hif1α and Vegfa expression mediated by β-catenin. However, Hif1α signaling pathway did not regulate tight junction proteins Claudin-5 and Occludin. Our data suggest that Wnt7a stimulation leads to a decrease in tight junction proteins mediated by the nuclear translocation of β-catenin, which hampers proper endothelial barrier formation. This process might be crucial in initiating endothelial cell proliferation and angiogenesis. Although HIF1α did not modulate the expression of tight junction proteins, it might play a role in brain angiogenesis and underlie pathogenic mechanisms in Wnt/HIF1α signaling in diseases such as cerebral small vessel disease.
Original languageEnglish
Number of pages15
JournalMolecular Neurobiology
Early online date26 Dec 2023
DOIs
Publication statusE-pub ahead of print - 26 Dec 2023

Bibliographical note

Funding
This work was supported by a PhD studentship, jointly funded by the University of Birmingham and CARIM, School for Cardiovascular Diseases Maastricht at Maastricht University.

Fingerprint

Dive into the research topics of 'Wnt7a Decreases Brain Endothelial Barrier Function Via β-Catenin Activation'. Together they form a unique fingerprint.

Cite this