Sema3E/PlexinD1 Inhibition is a Therapeutic Strategy for Improving Cerebral Perfusion and Restoring Functional Loss after Stroke in Aged Rats

Now with any brains at all in stroke we would follow this up with testing in humans, but that will never occur in our lifetimes. NO STROKE LEADERSHIP AND NO STROKE STRATEGY.

Sema3E/PlexinD1 Inhibition is a Therapeutic Strategy for Improving Cerebral Perfusion and Restoring Functional Loss after Stroke in Aged Rats

• Yi-Fan Zhou^{1, #},
• Peng-Cheng Li^{2, #},
• Jie-Hong Wu^{1, #},
• James Andrew Haslam³,
• Ling Mao¹,
• Yuan-Peng Xia¹,
• Quan-Wei He¹,
• Xu-Xia Wang⁴,
• Hao Lei⁴,
• Xiao-Li Lan⁵,
• Qing Robert Miao^{6, 7, 8},
• Zhen-Yu Yue⁹,

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Highlights

1.Sema3E as an endogenous inhibitor suppresses cerebral perfusion.

2.Unlike increasing VEGF, inhibiting Sema3E/PlexinD1 can improve the BBB integrity.

3.Sema3E suppresses both endothelial cell activity and pericytes recruitment.

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Abstract

Brain tissue survival and functional recovery following ischaemic stroke greatly depend on cerebral vessel perfusion and functional collateral circulation in the ischaemic 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 signalling is involved in poststroke neovascularization remains unknown. To determine the contribution of Sema3E/PlexinD1 signalling to poststroke recovery, aged rats (18 months) were subjected to a transient middle cerebral artery occlusion (tMCAO). We found that depletion of Sema3E/ PlexinD1 signalling with lentivirus-mediated PlexinD1-specific-shRNA improves tissue survival and functional outcome. Sema3E/PlexinD1 inhibition not only increases cortical perfusion but also ameliorates BBB damage, as determined by positron emission tomography (PET) and magnetic resonance imaging (MRI). Mechanistically, we demonstrated that Sema3E suppresses endothelial cell proliferation and angiogenic capacity. More importantly, Sema3E/ PlexinD1 signalling inhibits recruitment of pericytes by decreasing production of PDGF-BB in endothelial cells. Overall, our study revealed that inhibition of Sema3E/PlexinD1 signalling in the ischaemic penumbra, which increases both endothelial angiogenic capacity and recruitment of pericytes, contributed to functional neovascularization and BBB integrity in the aged rats. Our findings imply that Sema3E/PlexinD1 signalling is a novel therapeutic target for improving brain tissue survival and functional recovery post ischaemic stroke.

Key words

• ischaemic stroke;
• cerebral perfusion;
• functional neovascularization;
• BBB integrity;
• endothelial cells;
• pericytes

Abbreviation and Acronyms

• tMCAO, transient middle cerebral artery occlusion;
• Sema3E, Semaphorin 3E;
• VEGF, vascular endothelial growth factor;
• MRI, magnetic resonance imaging;
• PET, positron emission tomography;
• GFP, green fluorescent protein;
• BMVECs, brain microvascular endothelial cells;
• OGDR, oxygen glucose deprivation/reoxygenation;
• BBB, Blood-Brain Barrier;
• ECs, endothelial cells;
• CNS, central nervous system

Corresponding author. Department of Neurology Union Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan 430022, China. Tel:+86-13707114863; Fax: +86-27-85726028.

Corresponding author. Yanan Li, Department of Neurology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan 430022, China.Tel:+86-15871681596;Fax: +86-27-85726028.

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These authors contributed equally to this article.

© 2018 Elsevier Inc. All rights reserved.