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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\/\u03b2-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 \u03b2-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\/\u03b2-catenin mediated transcription to modulate the Wnt signaling pathway. The involvement of Wnt\/HIF1\u03b1 signaling was investigated by inhibiting Hif1\u03b1 signaling with <jats:italic>Hif1\u03b1<\/jats:italic> siRNA. Wnt7a stimulation led to activation and nuclear translocation of \u03b2-catenin, which was inhibited by XAV939. Wnt7a stimulation decreased Claudin-5 expression mediated by \u03b2-catenin and decreased endothelial barrier formation. Wnt7a increased <jats:italic>Hif1\u03b1<\/jats:italic> and <jats:italic>Vegfa<\/jats:italic> expression mediated by \u03b2-catenin. However, <jats:italic>Hif1\u03b1<\/jats:italic> 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 \u03b2-catenin, which hampers proper endothelial barrier formation. This process might be crucial in initiating endothelial cell proliferation and angiogenesis. Although HIF1\u03b1 did not modulate the expression of tight junction proteins, it might play a role in brain angiogenesis and underlie pathogenic mechanisms in Wnt\/HIF1\u03b1 signaling in diseases such as cerebral small vessel disease.<\/jats:p>","DOI":"10.1007\/s12035-023-03872-0","type":"journal-article","created":{"date-parts":[[2023,12,26]],"date-time":"2023-12-26T05:13:32Z","timestamp":1703567612000},"page":"4854-4867","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Wnt7a Decreases Brain Endothelial Barrier Function Via \u03b2-Catenin Activation"],"prefix":"10.1007","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0820-9322","authenticated-orcid":false,"given":"Narek","family":"Manukjan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Chau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Caiment","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"van Herwijnen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert J.","family":"Smeets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Fulton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6267-6442","authenticated-orcid":false,"given":"Zubair","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4375-0907","authenticated-orcid":false,"given":"W. 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