Synthetic VSMCs Induce BBB Disruption Mediated by MYPT1 in Ischemic Stroke

Abstract

Vascular smooth muscle cells (VSMCs) have been widely recognized as key players in regulating blood-brain barrier (BBB) function, their roles are unclear in ischemic stroke. Myosin phosphatase target subunit 1 (MYPT1) is essential for VSMCs contraction and contributes to maintaining healthy vasculature. We generated VSMC-specific MYPT1 knockout mice (MYPT1SMKO mice) and cultured VSMCs infected with Lv-shMYPT1 to explore BBB integrity, brain infarction and neurological deficits after ischemic stroke. 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 phenotypic switching of VSMCs and contributed to IL-6 expression. Knocking down ECSIT rescued the phenotypic switching of VSMCs and BBB disruption in ischemic stroke. Additionally, inhibition of IL-6 decreased BBB permeability. These findings reveal that MYPT1 deficiency activated phenotypic switching of VSMCs and induced BBB disruption after ischemic stroke through ECSIT-IL-6 signaling.