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In response to vascular injury, VSMCs would undergo phenotypic switching from a fully differentiated, low proliferative rate phenotype to a more pro\u2010proliferative, promigratory, and incompletely\u2010differentiated state. The lack of a full understanding of the molecular pathways coupling the vascular injury stimuli to VSMCs phenotype switching largely limits the development of medical therapies for treating intima hyperplasia\u2010related diseases. The role of signal transducers and activators of transcription 6 (STAT6) in modulating the proliferation and differentiation of various cell types, especially macrophage, has been well investigated, but little is known about its pathophysiological role and target genes in restenosis after vascular injury. In the present work, Stat6<jats:sup>\u2212\/\u2212<\/jats:sup> mice were observed to exhibit less severe intimal hyperplasia compared with Stat6<jats:sup>+\/+<\/jats:sup> mice after carotid injury. The expression of STAT6 was upregulated in VSMCs located in the injured vascular walls. STAT6 deletion leads to decreased proliferation and migration of VSMCs while STAT6 overexpression enhances the proliferation and migration of VSMCs companies with reduced expression of VSMCs marker genes and organized stress fibers. The effect of STAT6 in mouse VSMCs was conserved in human aortic SMCs. RNA\u2010deep\u2010sequencing and experiments verification revealed LncRNA C7orf69\/LOC100996318\u2010miR\u2010370\u20103p\/FOXO1\u2010ER stress signaling as the downstream network mediating the pro\u2010dedifferentiation effect of STAT6 in VSMCs. These findings broaden our understanding of vascular pathological molecules and throw a beam of light on the therapy of a variety of proliferative vascular diseases.<\/jats:p>","DOI":"10.1002\/cbin.12056","type":"journal-article","created":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T06:58:43Z","timestamp":1686553123000},"page":"1573-1588","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The downstream network of STAT6 in promoting vascular smooth muscle cell phenotypic switch and neointimal formation"],"prefix":"10.1002","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2649-8364","authenticated-orcid":false,"given":"Suling","family":"Ding","sequence":"first","affiliation":[{"name":"Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University Shanghai 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