Open AccessMfsd2a (Major Facilitator Superfamily Domain Containing 2a) Attenuates Intracerebral Hemorrhage–Induced Blood–Brain Barrier Disruption by Inhibiting Vesicular Transcytosis
Author(s) -
Yang YuanRui,
Xiong XiaoYi,
Liu Juan,
Wu LiRong,
Zhong Qi,
Zhou Kai,
Meng ZhaoYou,
Liu Liang,
Wang FaXiang,
Gong QiuWen,
Liao MaoFan,
Duan ChunMei,
Li Jie,
Yang MeiHua,
Zhang Qin,
Gong ChangXiong,
Yang QingWu
Publication year - 2017
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.117.005811
Subject(s) - major facilitator superfamily , transcytosis , blood–brain barrier , microbiology and biotechnology , vesicular transport protein , knockout mouse , vesicle , gene knockdown , intracerebral hemorrhage , transporter , endosome , medicine , chemistry , biology , biochemistry , endocytosis , central nervous system , receptor , gene , membrane , subarachnoid hemorrhage , intracellular
Background Blood–brain barrier ( BBB ) disruption aggravates brain injury induced by intracerebral hemorrhage ( ICH ); however, the mechanisms of BBB damage caused by ICH remain elusive. Mfsd2a (major facilitator superfamily domain containing 2a) has been known to play an essential role in BBB formation and function. In this study, we investigated the role and underlying mechanisms of Mfsd2a in BBB permeability regulation after ICH . Methods and Results Using ICH models, we found that Mfsd2a protein expression in perihematomal brain tissues was significantly decreased after ICH . Knockdown and knockout of Mfsd2a in mice markedly increased BBB permeability, neurological deficit score, and brain water contents after ICH , and these were rescued by overexpressing Mfsd2a in perihematomas. Moreover, we found that Mfsd2a regulation of BBB permeability after ICH correlated with changes in vesicle number. Expression profiling of tight junction proteins showed no differences in Mfsd2a knockdown, Mfsd2a knockout, and Mfsd2a overexpression mice. However, using electron microscopy following ICH , we observed a significant increase in pinocytotic vesicle number in Mfsd2a knockout mice and decreased the number of pinocytotic vesicles in mouse brains with Mfsd2a overexpression. Finally, using multiple reaction monitoring, we screened out 3 vesicle trafficking–related proteins (Srgap2, Stx7, and Sec22b) from 31 vesicle trafficking‐related proteins that were markedly upregulated in Mfsd2a knockout mice compared with controls after ICH . Conclusions In summary, our results suggest that Mfsd2a may protect against BBB injury by inhibiting vesicular transcytosis following ICH .