摘要
Blood-brain barrier(BBB)breakdown and the associated microvascular hyperpermeability are hallmark features of several neurological disorders,including traumatic brain injury(TBI).However,there is no viable therapeutic strategy to rescue BBB function.Tissue inhibitor of metalloproteinase-1(TIMP1)has been considered to be beneficial for vascular integrity,but the molecular mechanisms underlying the functions of TIMP1 remain elusive.Here,we report that TIMP1 executes a protective role on neuroprotective function via ameliorating BBB disruption in mice with experimental TBI.In human brain microvessel endothelial cells(HBMECs)exposed to hypoxia and inflammation injury,the recombinant TIMP1(rTIMP1)treatment maintained integrity of junctional proteins and trans-endothelial tightness.Mechanistically,TIMP1 interacts with CD63/integrinβ1 complex and activates downstream FAK signaling,leading to attenuation of RhoA activation and F-actin depolymerization for endothelial cells structure stabilization.Notably,these effects depend on CD63/integrinβ1 complex,instead of the MMP-inhibitory function.Together,our results identified a novel MMP-independent function of TIMP1 in regulating endothelial barrier integrity.Therapeutic interventions targeting TIMP1 and its downstream signaling may be beneficial to protect BBB function following brain injury and neurological disorders.
基金
supported by the grants from National Natural Science Foundation of China(Nos.81872855 and 81673420)
CAMS Innovation Fund for Medical Sciences(No.2017-I2M-2004,China)
National Science and Technology Major Project on Major New Drug Innovation of China(2018ZX09711001-003-005 and 2018ZX09711001-003-009)
Fundamental Research Funds for the Central Universities(3332019070,China)
Disciplines construction project(20190200802,China)
作者简介
Corresponding author:Ying Peng,Tel.:+861083165742,fax:+861063017757.E-mail address:ypeng@imm.ac.cn
