Faculty Collaboration Database

Sema3E/PlexinD1 inhibition is a therapeutic strategy for improving cerebral perfusion and restoring functional loss after stroke in aged rats. Neurobiol Aging 2018 Oct;70:102-116

Date

07/15/2018

Pubmed ID

30007159

DOI

10.1016/j.neurobiolaging.2018.06.003

Scopus ID

2-s2.0-85049463528 (requires institutional sign-in at Scopus site)   27 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.

Author List

Zhou YF, Li PC, Wu JH, Haslam JA, Mao L, Xia YP, He QW, Wang XX, Lei H, Lan XL, Miao QR, Yue ZY, Li YN, Hu B

MESH terms used to index this publication - Major topics in bold

Animals
Blood-Brain Barrier
Brain
Brain Ischemia
Male
Neovascularization, Pathologic
Nerve Tissue Proteins
Neuropilin-1
Rats, Sprague-Dawley
Receptors, Cell Surface
Recovery of Function
Semaphorin-3A
Signal Transduction
Stroke
Up-Regulation