Sema3E/PlexinD1 inhibition is a therapeutic strategy for improving cerebral perfusion and restoring functional loss after stroke in aged rats
Sema3E/PlexinD1 inhibition is a therapeutic strategy for improving cerebral perfusion and restoring functional loss after stroke in aged rats
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Sema3E/PlexinD1 抑制是改善老年大鼠脑灌注和恢复中风后功能丧失的治疗策略
DOI：
10.1016/j.neurobiolaging.2018.06.003
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发表时间：
2018-10
影响因子：
4.2
通讯作者：
Hu Bo
中科院分区：
文献类型：
--
作者：
Zhou Yi Fan;Li Peng Cheng;Wu Jie Hong;Haslam James Andrew;Mao Ling;Xia Yuan Peng;He Quan Wei;Wang Xu Xia;Lei Hao;Lan Xiao Li;Miao Qing Robert;Yue Zhen Yu;Li Ya Nan;Hu Bo
缺血性脑卒中后脑组织的存活和功能恢复在很大程度上依赖于缺血区的脑血管灌注和功能性侧支循环。脑信号蛋白3E（Semaphorin 3E，Sema 3E）是第三类分泌型脑信号蛋白之一，与其受体丛蛋白D1结合，在胚胎和出生后的血管形成中起着重要的调节作用。然而，Sema 3E/丛蛋白D1信号是否参与卒中后新生血管形成仍不清楚。为了确定Sema 3E/丛蛋白D1信号传导对中风后恢复的贡献，对老年大鼠（18个月）进行短暂的大脑中动脉闭塞。我们发现，用慢病毒介导的丛蛋白D1特异性shRNA消除Sema 3E/丛蛋白D1信号可以改善组织存活和功能结果。Sema 3E/丛蛋白D1抑制不仅增加皮质灌注，而且改善血脑屏障损伤，正电子发射断层扫描和磁共振成像确定。从机制上讲，我们证明了Sema 3E抑制内皮细胞增殖和血管生成能力。更重要的是，Sema 3E/丛蛋白D1信号通过减少内皮细胞中血小板衍生生长因子-BB的产生来抑制周细胞的募集。总的来说，我们的研究表明，抑制缺血半暗带中的Sema 3E/丛蛋白D1信号传导，增加内皮血管生成能力和周细胞的募集，有助于老年大鼠的功能性新血管形成和血脑屏障完整性。我们的研究结果表明，Sema 3E/PlexinD 1信号转导是改善缺血性卒中后脑组织存活和功能恢复的新的治疗靶点。
Brain tissue survival and functional recovery after ischemic stroke greatly depend on cerebral vessel perfusion and functional collateral circulation in the ischemic area. Semaphorin 3E (Sema3E), one of the class 3 secreted semaphorins, has been demonstrated to be a critical regulator in embryonic and postnatal vascular formation via binding to its receptor PlexinD1. However, whether Sema3E/PlexinD1 signaling is involved in poststroke neovascularization remains unknown. To determine the contribution of Sema3E/PlexinD1 signaling to poststroke recovery, aged rats (18 months) were subjected to a transient middle cerebral artery occlusion. We found that depletion of Sema3E/PlexinD1 signaling with lentivirus-mediated PlexinD1-specific-shRNA improves tissue survival and functional outcome. Sema3E/PlexinD1 inhibition not only increases cortical perfusion but also ameliorates blood-brain barrier damage, as determined by positron emission tomography and magnetic resonance imaging. Mechanistically, we demonstrated that Sema3E suppresses endothelial cell proliferation and angiogenic capacity. More importantly, Sema3E/PlexinD1 signaling inhibits recruitment of pericytes by decreasing production of platelet derived growth factor-BB in endothelial cells. Overall, our study revealed that inhibition of Sema3E/PlexinD1 signaling in the ischemic penumbra, which increases both endothelial angiogenic capacity and recruitment of pericytes, contributed to functional neovascularization and blood-brain barrier integrity in the aged rats. Our findings imply that Sema3E/PlexinD1 signaling is a novel therapeutic target for improving brain tissue survival and functional recovery after ischemic stroke.
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影响因子：
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作者：
Dohgu, S;Takata, F;Kataoka, Y
通讯作者：
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