Sema3E/PlexinD1 inhibition is a therapeutic strategy for improving cerebral perfusion and restoring functional loss after stroke in aged rats

Yi Fan Zhou, Peng Cheng Li, Jie Hong Wu, James Andrew Haslam, Ling Mao, Yuan Peng Xia, Quan Wei He, Xu Xia Wang, Hao Lei, Xiao Li Lan, Qing Robert Miao, Zhen Yu Yue, Ya Nan Li, Bo Hu

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)102-116
Number of pages15
JournalNeurobiology of Aging
Volume70
DOIs
StatePublished - Oct 2018

Keywords

  • BBB integrity
  • Cerebral perfusion
  • Endothelial cells
  • Functional neovascularization
  • Ischemic stroke
  • Pericytes

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