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

doi:10.1016/j.isci.2021.103047

Synthetic VSMCs induce BBB disruption mediated by MYPT1 in ischemic stroke

iScience. 2021 Aug 28;24(9):103047. doi: 10.1016/j.isci.2021.103047. eCollection 2021 Sep 24.

Authors

Hailan Meng^{1

2

3

4

5}, Lizhen Fan^{1

2

3

4

5}, Cun-Jin Zhang^{1

2

3

4

5}, Liwen Zhu^{1

2

3

4

5}, Pinyi Liu^{1

2

3

4

5}, Jian Chen^{1

2

3

4

5}, Xinyu Bao^{1

2

3

4

5}, Zhijun Pu^{1

2

3

4

5}, Min-Sheng Zhu^{6

7}, Yun Xu^{1

2

3

4

5}

Affiliations

¹ Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, China.
² Institute of Brain Sciences, Nanjing University, Nanjing 210008, China.
³ Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China.
⁴ Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing 210008, China.
⁵ Nanjing Neuropsychiatry Clinic Medical Center, Nanjing 210008, China.
⁶ Model Animal Research Center, Nanjing University, Nanjing 210061, China.
⁷ Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China.

Abstract

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 (MYPT1^SMKO) 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.

Keywords: Cell biology; Immunology; Molecular physiology; Proteomics.