TIMP1 preserves the blood-brain barrier through interacting with CD63/integrin 1 complex and regulating downstream FAK/RhoA signaling.
10.1016/j.apsb.2020.02.015
- Author:
Jingshu TANG
1
;
Yuying KANG
1
;
Longjian HUANG
1
;
Lei WU
1
;
Ying PENG
1
Author Information
1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
- Publication Type:Journal Article
- Keywords:
AJ, adherent junction;
BBB, blood–brain barrier;
Blood–brain barrier;
CD63;
CNS, central nervous system;
EC, endothelial cells;
HBMEC, human brain microvessel endothelial cell;
Integrin β1;
Junctional proteins;
MMP9, matrix metalloproteinase-9;
TBI, traumatic brain injury;
TIMP1, tissue inhibitors of metalloproteinases-1;
TJ, tight junction;
Tissue inhibitor of metalloproteinase-1
- From:
Acta Pharmaceutica Sinica B
2020;10(6):987-1003
- CountryChina
- Language:English
-
Abstract:
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 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/integrin 1 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/integrin 1 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.
