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Vascular endothelial growth factor (VEGF) promotes the transformation of reactive astrocytes into neurons in ischemic brain. Therefore, in this study, the molecular mechanism of VEGF's effect on ischemia\/hypoxia\u2010induced astrocyte to neuron transformation was investigated in the models of rat middle cerebral artery occlusion (MCAO) and in astrocyte culture with oxygen and glucose deprivation (OGD). We found that VEGF enhanced ischemia\u2010induced Pax6, a neurogenic fate determinant, expression and Erk phosphorylation in reactive astrocytes and reduced infarct volume of rat brain at 3\u2009days after MCAO, which effects could be blocked by administration of U0126, a MAPK\/Erk inhibitor. In cultured astrocytes, VEGF also enhanced OGD\u2010induced Erk phosphorylation and Pax6 expression, which was blocked by U0126, but not wortmannin, a PI3K\/Akt inhibitor, or SB203580, a MAPK\/p38 inhibitor, suggesting VEGF enhanced Pax6 expression via activation of MAPK\/Erk pathway. OGD induced the increase of miR365 and VEGF inhibited the increase of OGD\u2010induced miR365 expression. However, miR365 agonists blocked VEGF\u2010enhanced Pax6 expression in hypoxic astrocytes, but did not block VEGF\u2010enhanced Erk phosphorylation. We further found that VEGF promoted OGD\u2010induced astrocyte\u2010converted to neuron. Interestingly, both U0126 and Pax6 RNAi significantly reduced enhancement of VEGF on astrocytes\u2010to\u2010neurons transformation, as indicated Dcx and MAP2 immunopositive signals in reactive astrocytes. Moreover, those transformed neurons become mature and functional. We concluded that VEGF enhanced astrocytic neurogenesis via the MAPK\/Erk\u2010miR\u2010365\u2010Pax6 signal axis. The results also indicated that astrocytes play important roles in the reconstruction of neurovascular units in brain after stroke.<\/jats:p>","DOI":"10.1002\/glia.24361","type":"journal-article","created":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T03:11:01Z","timestamp":1679627461000},"page":"1648-1666","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Vascular endothelial growth factor promotes transdifferentiation of astrocytes into neurons via activation of the\n                    <scp>MAPK<\/scp>\n                    \/\n                    <scp>Erk\u2010Pax6<\/scp>\n                    signal pathway"],"prefix":"10.1002","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5085-5276","authenticated-orcid":false,"given":"Yu","family":"Lei","sequence":"first","affiliation":[{"name":"Department of Neurobiology and Research Institute for Aging and Medicine, School of Basic Medical Sciences, Shanghai Medical College Fudan University  Shanghai 200032 People's Republic of China"},{"name":"National Clinical Research Center for Aging and Medicine, Shanghai Medical College Fudan University  Shanghai 200032 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Research Institute for Aging and Medicine, School of Basic Medical Sciences, Shanghai Medical College Fudan University  Shanghai 200032 People's Republic of China"},{"name":"National Clinical Research Center for Aging and Medicine, Shanghai Medical College Fudan University  Shanghai 200032 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010Lin","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Research Institute for Aging and Medicine, School of Basic Medical Sciences, Shanghai Medical College Fudan University  Shanghai 200032 People's Republic of China"},{"name":"National Clinical Research Center for Aging and Medicine, Shanghai Medical College Fudan University  Shanghai 200032 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling\u2010Ling","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Research Institute for Aging and Medicine, School of Basic Medical Sciences, Shanghai Medical College Fudan University  Shanghai 200032 People's Republic of China"},{"name":"National Clinical Research Center for Aging and Medicine, Shanghai Medical College Fudan University  Shanghai 200032 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeng\u2010Wei","family":"Kou","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Research Institute for Aging and Medicine, School of Basic Medical Sciences, Shanghai Medical College Fudan University  Shanghai 200032 People's Republic of China"},{"name":"National Clinical Research Center for Aging and Medicine, Shanghai Medical College Fudan University  Shanghai 200032 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0027-3386","authenticated-orcid":false,"given":"Feng\u2010Yan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Research Institute for Aging and Medicine, School of Basic Medical Sciences, Shanghai Medical College Fudan University  Shanghai 200032 People's Republic of China"},{"name":"National Clinical Research Center for Aging and Medicine, Shanghai Medical College Fudan University  Shanghai 200032 People's Republic of China"},{"name":"Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences and Institute of Biomedical Sciences, Shanghai Medical College Fudan University  Shanghai 200032 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,3,24]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2005.05.011"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1159\/000049122"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-02-00664.1999"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm747"},{"issue":"4","key":"e_1_2_8_6_1","first-page":"313","article-title":"Intraventricular vascular endothelial growth factor antibody increases infarct volume following transient cerebral ischemia","volume":"20","author":"Bao W. 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