Vascular Sema3E-Plexin-D1 Signaling Reactivation Promotes Post-stroke Recovery through VEGF Downregulation in Mice.
Vascular Sema3E-Plexin-D1 Signaling Reactivation Promotes Post-stroke Recovery through VEGF Downregulation in Mice.
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DOI：
10.1007/s12975-021-00914-4
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发表时间：
2022-03
影响因子：
6.9
通讯作者：
Oh WJ
中科院分区：
文献类型：
--
作者：
Yu R;Kim NS;Li Y;Jeong JY;Park SJ;Zhou B;Oh WJ
中风后血管重塑，包括血管生成，有助于功能恢复。适当的血管修复对于中风后的有效恢复非常重要；然而，协调参与血管重塑的不同信号通路的潜在机制仍然很大程度上未知。最近，轴突引导分子被揭示为受伤血管重塑的关键参与者。其中一种分子 Semaphorin 3E (Sema3E) 及其受体 Plexin-D1 通过调节血管内皮生长因子 (VEGF) 信号传导来控制血管发育。在本研究中，我们使用短暂性脑梗塞的小鼠模型，旨在研究 Sema3E-Plexin-D1 信号传导是否参与缺血性损伤后的脑血管重塑。我们发现缺血性损伤迅速诱导梗死周围区域神经元中的 Sema3e 表达，随后重塑血管中 Plexin-D1 上调。有趣的是，Plexin-D1 重新出现与脑血管进入活跃的血管生成过程同时发生。与此相一致的是，Plxnd1 消融使神经功能缺陷、梗塞体积、神经元存活率和血流恢复恶化。此外，血管形态发生减少和异常是由 VEGF 信号传导异常增加引起的。在 Plxnd1 敲除小鼠中，我们观察到静脉注射示踪剂在脑实质中显着外渗、连接蛋白下调以及再生血管中的错误定位。这表明 Sema3E-Plexin-D1 信号传导的缺失与血脑屏障 (BBB) 损伤有关。最后，在血管重塑过程中抑制 VEGF 信号传导后，Plxnd1 敲除小鼠的异常行为表现、异常血管表型和 BBB 分解缺陷得到恢复。这些发现表明，Sema3E-Plexin-D1 信号传导可以通过下调受损成人大脑中的 VEGF 信号传导来促进功能恢复。在线版本包含可在 10.1007/s12975-021-00914-4 获取的补充材料。
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. The online version contains supplementary material available at 10.1007/s12975-021-00914-4.
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影响因子：
5.6
作者：
Geiseler SJ;Morland C
通讯作者：
Morland C
影响因子：
11.8
作者：
Gitler, AD;Lu, MM;Epstein, JA
通讯作者：
Epstein, JA
发育和病理过程中的脑血管生成：中风后神经血管损伤和血管生成恢复。
DOI：
10.1111/j.1742-4658.2009.07176.x
发表时间：
2009-09
期刊：
The FEBS journal
影响因子：
--
作者：
Arai K;Jin G;Navaratna D;Lo EH
通讯作者：
Lo EH
DOI：
10.1161/atvbaha.116.308620
发表时间：
2017-05-01
影响因子：
8.7
作者：
Ghori, Adnan;Freimann, Florian B.;Vajkoczy, Peter
通讯作者：
Vajkoczy, Peter
影响因子：
11.1
作者：
del Zoppo GJ
通讯作者：
del Zoppo GJ