Mfsd2a (Major Facilitator Superfamily Domain Containing 2a) Attenuates Intracerebral Hemorrhage–Induced Blood–Brain Barrier Disruption by Inhibiting Vesicular Transcytosis

Abstract

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.

DOI: 10.1161/JAHA.117.005811

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Cite this paper

@inproceedings{Yang2017Mfsd2aF, title={Mfsd2a (Major Facilitator Superfamily Domain Containing 2a) Attenuates Intracerebral Hemorrhage–Induced Blood–Brain Barrier Disruption by Inhibiting Vesicular Transcytosis}, author={Y Yang and Xiao‐Yi Xiong and Juan Liu and L. Wu and Qi Zhong and Kai Zhou and Zhao‐You Meng and Liang Liu and F. Wang and Q Gong and Mao‐Fan Liao and Chun‐Mei Duan and Jie Li and Mei‐Hua Yang and Qin Zhang and C Gong and Q Yang}, booktitle={Journal of the American Heart Association}, year={2017} }