TIMP1 preserves the blood-brain barrier through interacting with CD63/integrin ß 1 complex and regulating downstream FAK/RhoA signaling.
Acta Pharm Sin B
; 10(6): 987-1003, 2020 Jun.
Article
em En
| MEDLINE
| ID: mdl-32642407
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 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/integrin ß1 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 ß1 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.
AJ, adherent junction; BBB, bloodbrain barrier; Bloodbrain barrier; CD63; CNS, central nervous system; EC, endothelial cells; HBMEC, human brain microvessel endothelial cell; Integrin ß1; Junctional proteins; MMP9, matrix metalloproteinase-9; TBI, traumatic brain injury; TIMP1, tissue inhibitors of metalloproteinases-1; TJ, tight junction; Tissue inhibitor of metalloproteinase-1
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Acta Pharm Sin B
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China