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In this study, we show that TGF-\u03b2 activates the endothelial-to-mesenchymal transition (EndMT) in cultured human aortic endothelial cells (HAECs) and this transition is dependent on the key executor of the Wnt signaling pathway <jats:italic>in vitro<\/jats:italic>. This study presents the first evidence describing the mechanistic details of the TGF-\u03b2-induced EndMT signaling pathway in HAECs by documenting the cellular transition to the mesenchymal phenotype including the expression of mesenchymal markers \u03b1-SMA and PDGFR\u03b1, and the loss of endothelial markers including VE-cadherin and CD31. Furthermore, a short hairpin RNA (shRNA) screening revealed that Wnt2 signaling is required for TGF-\u03b2-mediated EndMT of HAECs. Also, we found that LDLR<jats:sup>\u2212\/\u2212<\/jats:sup> mice fed on a high-fat western-type diet (21% fat, 0.2% cholesterol) expressed high levels of Wnt2 protein in atherosclerotic lesions, confirming that this signaling pathway is involved in atherosclerosis <jats:italic>in vivo<\/jats:italic>. These findings suggest that Wnt2 may contribute to atherosclerotic plaque development and this study will render Wnt2 as a potential target for therapeutic intervention aiming at controlling atherosclerosis.<\/jats:p>","DOI":"10.3389\/fcvm.2021.751720","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T20:35:43Z","timestamp":1638304543000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Wnt2 Contributes to the Development of Atherosclerosis"],"prefix":"10.3389","volume":"8","author":[{"given":"Jinyu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Rojas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip 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