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The increased permeability of choroid plexus and breakdown of the blood\u2013brain barrier (BBB) was reported as a prominent mechanism of IVH-induced hydrocephalus, and vascular endothelial\u2013cadherin (VE\u2013cadherin) was demonstrated to be relevant. Metformin was reported to protect endothelial junction and preserve permeability widely; however, its role in hydrocephalus remains unclear. In this study, the decreased expression of VE\u2013cadherin in the choroid plexus, accompanied with ventricle dilation, was investigated in an IVH rat model induced by intraventricular injection of autologous blood. Metformin treatment ameliorated hydrocephalus and upregulated VE\u2013cadherin expression in choroid plexus meanwhile. We then observed that the internalization of VE\u2013cadherin caused by the activation of vascular endothelial growth factor (VEGF) signaling after IVH was related to the occurrence of hydrocephalus, whereas it can be reversed by metformin treatment. Restraining VEGF signaling by antagonizing VEGFR2 or inhibiting Src phosphorylation increased the expression of VE\u2013cadherin and decreased the severity of hydrocephalus after IVH. Our study demonstrated that the internalization of VE\u2013cadherin via the activation of VEGF signaling may contribute to IVH-induced hydrocephalus, and metformin may be a potential protector via suppressing this pathway.<\/jats:p>","DOI":"10.3390\/ijms23158552","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T23:49:27Z","timestamp":1659397767000},"page":"8552","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Metformin Preserves VE\u2013Cadherin in Choroid Plexus and Attenuates Hydrocephalus via VEGF\/VEGFR2\/p-Src in an Intraventricular Hemorrhage Rat Model"],"prefix":"10.3390","volume":"23","author":[{"given":"Dan","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianghua","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodi","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China"},{"name":"Department of Neurology, Henan Province People\u2019s Hospital, People\u2019s Hospital of Zhengzhou University, Zhengzhou 450000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luhang","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lusha","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1161\/STROKEAHA.108.535419","article-title":"Intraventricular hemorrhage: Severity factor and treatment target in spontaneous intracerebral hemorrhage","volume":"40","author":"Hanley","year":"2009","journal-title":"Stroke"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"217","DOI":"10.3389\/fneur.2019.00217","article-title":"Intraventricular Hemorrhage Severity as a Predictor of Outcome in Intracerebral Hemorrhage","volume":"10","author":"Trifan","year":"2019","journal-title":"Front. 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