Vascular Sema3E-Plexin-D1 Signaling Reactivation Promotes Post-stroke Recovery through VEGF Downregulation in Mice

Post-stroke vascular remodeling, including angiogenesis, facilitates functional recovery. Proper vascular repair is important for efficient post-stroke recovery; however, the underlying mechanisms coordinating the diverse signaling pathways involved in vascular remodeling remain largely unknown. Rec...

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Autores principales: Yu, Ri, Kim, Nam-Suk, Li, Yan, Jeong, Jin-Young, Park, Sang-Joon, Zhou, Bin, Oh, Won-Jong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8766426/
https://www.ncbi.nlm.nih.gov/pubmed/33978913
http://dx.doi.org/10.1007/s12975-021-00914-4
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author Yu, Ri
Kim, Nam-Suk
Li, Yan
Jeong, Jin-Young
Park, Sang-Joon
Zhou, Bin
Oh, Won-Jong
author_facet Yu, Ri
Kim, Nam-Suk
Li, Yan
Jeong, Jin-Young
Park, Sang-Joon
Zhou, Bin
Oh, Won-Jong
author_sort Yu, Ri
collection PubMed
description Post-stroke vascular remodeling, including angiogenesis, facilitates functional recovery. Proper vascular repair is important for efficient post-stroke recovery; however, the underlying mechanisms coordinating the diverse signaling pathways involved in vascular remodeling remain largely unknown. Recently, axon guidance molecules were revealed as key players in injured vessel remodeling. One such molecule, Semaphorin 3E (Sema3E), and its receptor, Plexin-D1, control vascular development by regulating vascular endothelial growth factor (VEGF) signaling. In this study, using a mouse model of transient brain infarction, we aimed to investigate whether Sema3E-Plexin-D1 signaling was involved in cerebrovascular remodeling after ischemic injury. We found that ischemic damage rapidly induced Sema3e expression in the neurons of peri-infarct regions, followed by Plexin-D1 upregulation in remodeling vessels. Interestingly, Plexin-D1 reemergence was concurrent with brain vessels entering an active angiogenic process. In line with this, Plxnd1 ablation worsened neurological deficits, infarct volume, neuronal survival rate, and blood flow recovery. Furthermore, reduced and abnormal vascular morphogenesis was caused by aberrantly increased VEGF signaling. In Plxnd1 knockout mice, we observed significant extravasation of intravenously administered tracers in the brain parenchyma, junctional protein downregulation, and mislocalization in regenerating vessels. This suggested that the absence of Sema3E-Plexin-D1 signaling is associated with blood–brain barrier (BBB) impairment. Finally, the abnormal behavioral performance, aberrant vascular phenotype, and BBB breakdown defects in Plxnd1 knockout mice were restored following the inhibition of VEGF signaling during vascular remodeling. These findings demonstrate that Sema3E-Plexin-D1 signaling can promote functional recovery by downregulating VEGF signaling in the injured adult brain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12975-021-00914-4.
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spelling pubmed-87664262022-02-02 Vascular Sema3E-Plexin-D1 Signaling Reactivation Promotes Post-stroke Recovery through VEGF Downregulation in Mice Yu, Ri Kim, Nam-Suk Li, Yan Jeong, Jin-Young Park, Sang-Joon Zhou, Bin Oh, Won-Jong Transl Stroke Res Original Article Post-stroke vascular remodeling, including angiogenesis, facilitates functional recovery. Proper vascular repair is important for efficient post-stroke recovery; however, the underlying mechanisms coordinating the diverse signaling pathways involved in vascular remodeling remain largely unknown. Recently, axon guidance molecules were revealed as key players in injured vessel remodeling. One such molecule, Semaphorin 3E (Sema3E), and its receptor, Plexin-D1, control vascular development by regulating vascular endothelial growth factor (VEGF) signaling. In this study, using a mouse model of transient brain infarction, we aimed to investigate whether Sema3E-Plexin-D1 signaling was involved in cerebrovascular remodeling after ischemic injury. We found that ischemic damage rapidly induced Sema3e expression in the neurons of peri-infarct regions, followed by Plexin-D1 upregulation in remodeling vessels. Interestingly, Plexin-D1 reemergence was concurrent with brain vessels entering an active angiogenic process. In line with this, Plxnd1 ablation worsened neurological deficits, infarct volume, neuronal survival rate, and blood flow recovery. Furthermore, reduced and abnormal vascular morphogenesis was caused by aberrantly increased VEGF signaling. In Plxnd1 knockout mice, we observed significant extravasation of intravenously administered tracers in the brain parenchyma, junctional protein downregulation, and mislocalization in regenerating vessels. This suggested that the absence of Sema3E-Plexin-D1 signaling is associated with blood–brain barrier (BBB) impairment. Finally, the abnormal behavioral performance, aberrant vascular phenotype, and BBB breakdown defects in Plxnd1 knockout mice were restored following the inhibition of VEGF signaling during vascular remodeling. These findings demonstrate that Sema3E-Plexin-D1 signaling can promote functional recovery by downregulating VEGF signaling in the injured adult brain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12975-021-00914-4. Springer US 2021-05-12 2022 /pmc/articles/PMC8766426/ /pubmed/33978913 http://dx.doi.org/10.1007/s12975-021-00914-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Yu, Ri
Kim, Nam-Suk
Li, Yan
Jeong, Jin-Young
Park, Sang-Joon
Zhou, Bin
Oh, Won-Jong
Vascular Sema3E-Plexin-D1 Signaling Reactivation Promotes Post-stroke Recovery through VEGF Downregulation in Mice
title Vascular Sema3E-Plexin-D1 Signaling Reactivation Promotes Post-stroke Recovery through VEGF Downregulation in Mice
title_full Vascular Sema3E-Plexin-D1 Signaling Reactivation Promotes Post-stroke Recovery through VEGF Downregulation in Mice
title_fullStr Vascular Sema3E-Plexin-D1 Signaling Reactivation Promotes Post-stroke Recovery through VEGF Downregulation in Mice
title_full_unstemmed Vascular Sema3E-Plexin-D1 Signaling Reactivation Promotes Post-stroke Recovery through VEGF Downregulation in Mice
title_short Vascular Sema3E-Plexin-D1 Signaling Reactivation Promotes Post-stroke Recovery through VEGF Downregulation in Mice
title_sort vascular sema3e-plexin-d1 signaling reactivation promotes post-stroke recovery through vegf downregulation in mice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8766426/
https://www.ncbi.nlm.nih.gov/pubmed/33978913
http://dx.doi.org/10.1007/s12975-021-00914-4
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