Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 39, Issue 8, Pages 1501-1515Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X18769515
Keywords
Blood-brain barrier; cerebral ischemia; pericyte; platelet-derived growth factor receptor-beta; transforming growth factor-beta
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Funding
- National Natural Science Foundation of China [81360186, 81460190]
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Core Research for Evolutional Science and Technology, Japan Science and Technology Agency (CREST, JST) [20390108, 20590381, 24790378]
- Grants-in-Aid for Scientific Research [17H04062] Funding Source: KAKEN
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Although platelet-derived growth factor receptor beta (PDGFR-beta) 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-beta(floxed/floxed) mice (Floxed), postnatally induced systemic PDGFR-beta 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-beta (TGF-beta) 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-beta gene expression in pericytes, and was additively improved by PDGFR-beta and TGF-beta receptor signals under hypoxia condition. Exogenous PDGF-BB increased the expression of p-Smad2/3, while anti-TGF-beta 1 antibody at least partially inhibited the phosphorylation of Smad2/3 after PDGF-BB treatment in vitro. Furthermore, pre-administration of TGF-beta 1 partially alleviated edema formation, neurologic dysfunction, and TJs reduction in Esr-KO mice after MCAO. Accordingly, PDGFR-beta signalling, via TGF-beta signalling, may be crucial for restoration of BBB integrity after cerebral ischemia and therefore represents a novel potential therapeutic target.
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