TY - JOUR
T1 - PDGFR-β restores blood-brain barrier functions in a mouse model of focal cerebral ischemia
AU - Shen, Jie
AU - Xu, Guihua
AU - Zhu, Runxiu
AU - Yuan, Jun
AU - Ishii, Yoko
AU - Hamashima, Takeru
AU - Matsushima, Takako
AU - Yamamoto, Seiji
AU - Takatsuru, Yusuke
AU - Nabekura, Junichi
AU - Sasahara, Masakiyo
N1 - Publisher Copyright:
© The Author(s) 2018.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - Although platelet-derived growth factor receptor beta (PDGFR-β) mediates the recruitment of vascular pericytes into ischemic lesion to restore the blood-brain barrier (BBB) dysfunction, its mechanisms still remain elusive. Compared with control PDGFR-βfloxed/floxed mice (Floxed), postnatally induced systemic PDGFR-β knockout mice (Esr-KO) not only showed severe brain edema, neurologic functional deficits, decreased expression of tight junction (TJ) proteins, abundant endothelial transcytosis, and deformed TJs in the BBB, but also showed reduced expression of transforming growth factor-β (TGF-β) protein after photothrombotic middle cerebral artery occlusion (MCAO). In endothelial-pericyte co-culture, an in vitro model of BBB, the increment in the barrier function of endothelial monolayer induced by pericyte co-culture was completely cancelled by silencing PDGFR-β gene expression in pericytes, and was additively improved by PDGFR-β and TGF-β receptor signals under hypoxia condition. Exogenous PDGF-BB increased the expression of p-Smad2/3, while anti-TGF-β1 antibody at least partially inhibited the phosphorylation of Smad2/3 after PDGF-BB treatment in vitro. Furthermore, pre-administration of TGF-β1 partially alleviated edema formation, neurologic dysfunction, and TJs reduction in Esr-KO mice after MCAO. Accordingly, PDGFR-β signalling, via TGF-β signalling, may be crucial for restoration of BBB integrity after cerebral ischemia and therefore represents a novel potential therapeutic target.
AB - Although platelet-derived growth factor receptor beta (PDGFR-β) mediates the recruitment of vascular pericytes into ischemic lesion to restore the blood-brain barrier (BBB) dysfunction, its mechanisms still remain elusive. Compared with control PDGFR-βfloxed/floxed mice (Floxed), postnatally induced systemic PDGFR-β knockout mice (Esr-KO) not only showed severe brain edema, neurologic functional deficits, decreased expression of tight junction (TJ) proteins, abundant endothelial transcytosis, and deformed TJs in the BBB, but also showed reduced expression of transforming growth factor-β (TGF-β) protein after photothrombotic middle cerebral artery occlusion (MCAO). In endothelial-pericyte co-culture, an in vitro model of BBB, the increment in the barrier function of endothelial monolayer induced by pericyte co-culture was completely cancelled by silencing PDGFR-β gene expression in pericytes, and was additively improved by PDGFR-β and TGF-β receptor signals under hypoxia condition. Exogenous PDGF-BB increased the expression of p-Smad2/3, while anti-TGF-β1 antibody at least partially inhibited the phosphorylation of Smad2/3 after PDGF-BB treatment in vitro. Furthermore, pre-administration of TGF-β1 partially alleviated edema formation, neurologic dysfunction, and TJs reduction in Esr-KO mice after MCAO. Accordingly, PDGFR-β signalling, via TGF-β signalling, may be crucial for restoration of BBB integrity after cerebral ischemia and therefore represents a novel potential therapeutic target.
KW - Blood-brain barrier
KW - cerebral ischemia
KW - pericyte
KW - platelet-derived growth factor receptor-beta
KW - transforming growth factor-β
UR - http://www.scopus.com/inward/record.url?scp=85045151408&partnerID=8YFLogxK
U2 - 10.1177/0271678X18769515
DO - 10.1177/0271678X18769515
M3 - 学術論文
C2 - 29629621
AN - SCOPUS:85045151408
SN - 0271-678X
VL - 39
SP - 1501
EP - 1515
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
IS - 8
ER -