Synthetic VSMCs induce BBB disruption mediated by MYPT1 in ischemic stroke
Hailan Meng,
Lizhen Fan,
Cun-Jin Zhang,
Liwen Zhu,
Pinyi Liu,
Jian Chen,
Xinyu Bao,
Zhijun Pu,
Min-Sheng Zhu,
Yun Xu
Affiliations
Hailan Meng
Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, China; Institute of Brain Sciences, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing 210008, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing 210008, China
Lizhen Fan
Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, China; Institute of Brain Sciences, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing 210008, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing 210008, China
Cun-Jin Zhang
Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, China; Institute of Brain Sciences, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing 210008, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing 210008, China
Liwen Zhu
Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, China; Institute of Brain Sciences, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing 210008, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing 210008, China
Pinyi Liu
Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, China; Institute of Brain Sciences, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing 210008, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing 210008, China
Jian Chen
Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, China; Institute of Brain Sciences, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing 210008, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing 210008, China
Xinyu Bao
Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, China; Institute of Brain Sciences, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing 210008, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing 210008, China
Zhijun Pu
Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, China; Institute of Brain Sciences, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing 210008, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing 210008, China
Min-Sheng Zhu
Model Animal Research Center, Nanjing University, Nanjing 210061, China; Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
Yun Xu
Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, China; Institute of Brain Sciences, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing 210008, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing 210008, China; Corresponding author
Summary: Vascular smooth muscle cells (VSMCs) have been widely recognized as key players in regulating blood-brain barrier (BBB) function, and their roles are unclear in ischemic stroke. Myosin phosphatase target subunit 1 (MYPT1) is essential for VSMC contraction and maintaining healthy vasculature. We generated VSMC-specific MYPT1 knockout (MYPT1SMKO) mice and cultured VSMCs infected with Lv-shMYPT1 to explore phenotypic switching of VSMCs and the accompanied impacts on BBB integrity. We found that MYPT1 deficiency induced phenotypic switching of synthetic VSMCs, which aggravated BBB disruption. Proteomic analysis identified evolutionarily conserved signaling intermediates in Toll pathways (ECSIT) as a downstream molecule that promotes activation of synthetic VSMCs and contributed to IL-6 expression. Knocking down ECSIT rescued phenotypic switching of VSMCs and BBB disruption. Additionally, inhibition of IL-6 decreased BBB permeability. These findings reveal that MYPT1 deficiency activated phenotypic switching of synthetic VSMCs and induced BBB disruption through ECSIT-IL-6 signaling after ischemic stroke.
