PMID- 33859779
OWN - NLM
STAT- MEDLINE
DCOM- 20210609
LR  - 20230330
IS  - 1942-0994 (Electronic)
IS  - 1942-0900 (Print)
IS  - 1942-0994 (Linking)
VI  - 2021
DP  - 2021
TI  - Increase in Blood-Brain Barrier (BBB) Permeability Is Regulated by MMP3 via the 
      ERK Signaling Pathway.
PG  - 6655122
LID - 10.1155/2021/6655122 [doi]
LID - 6655122
AB  - BACKGROUND: The blood-brain barrier (BBB) regulates the exchange of molecules 
      between the brain and peripheral blood and is composed primarily of microvascular 
      endothelial cells (BMVECs), which form the lining of cerebral blood vessels and 
      are linked via tight junctions (TJs). The BBB is regulated by components of the 
      extracellular matrix (ECM), and matrix metalloproteinase 3 (MMP3) remodels the 
      ECM's basal lamina, which forms part of the BBB. Oxidative stress is implicated 
      in activation of MMPs and impaired BBB. Thus, we investigated whether MMP3 
      modulates BBB permeability. METHODS: Experiments included in vivo assessments of 
      isoflurane anesthesia and dye extravasation from brain in wild-type (WT) and 
      MMP3-deficient (MMP3-KO) mice, as well as in vitro assessments of the integrity 
      of monolayers of WT and MMP3-KO BMVECs and the expression of junction proteins. 
      RESULTS: Compared to WT mice, measurements of isoflurane usage and anesthesia 
      induction time were higher in MMP3-KO mice and lower in WT that had been treated 
      with MMP3 (WT+MMP3), while anesthesia emergence times were shorter in MMP3-KO 
      mice and longer in WT+MMP3 mice than in WT. Extravasation of systemically 
      administered dyes was also lower in MMP3-KO mouse brains and higher in WT+MMP3 
      mouse brains, than in the brains of WT mice. The results from both TEER and 
      Transwell assays indicated that MMP3 deficiency (or inhibition) increased, while 
      MMP3 upregulation reduced barrier integrity in either BMVEC or the coculture. 
      MMP3 deficiency also increased the abundance of TJs and VE-cadherin proteins in 
      BMVECs, and the protein abundance declined when MMP3 activity was upregulated in 
      BMVECs, but not when the cells were treated with an inhibitor of extracellular 
      signal related-kinase (ERK). CONCLUSION: MMP3 increases BBB permeability 
      following the administration of isoflurane by upregulating the ERK signaling 
      pathway, which subsequently reduces TJ and VE-cadherin proteins in BMVECs.
CI  - Copyright (c) 2021 Qin Zhang et al.
FAU - Zhang, Qin
AU  - Zhang Q
AD  - Department of Biological Sciences Division-Cardiology, University of Chicago, 
      USA.
AD  - Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, China.
FAU - Zheng, Mei
AU  - Zheng M
AD  - Department of Biological Sciences Division-Cardiology, University of Chicago, 
      USA.
FAU - Betancourt, Cristian E
AU  - Betancourt CE
AD  - Department of Biological Sciences Division-Cardiology, University of Chicago, 
      USA.
FAU - Liu, Lifeng
AU  - Liu L
AD  - Department of Biological Sciences Division-Cardiology, University of Chicago, 
      USA.
FAU - Sitikov, Albert
AU  - Sitikov A
AD  - Department of Biological Sciences Division-Cardiology, University of Chicago, 
      USA.
FAU - Sladojevic, Nikola
AU  - Sladojevic N
AD  - Department of Biological Sciences Division-Cardiology, University of Chicago, 
      USA.
FAU - Zhao, Qiong
AU  - Zhao Q
AD  - Division of Cardiology, Department of Medicine, Inova Heart and Vascular 
      Institute, USA.
FAU - Zhang, John H
AU  - Zhang JH
AUID- ORCID: 0000-0002-4319-4285
AD  - Center for Neuroscience Research, Loma Linda University, School of Medicine, USA.
FAU - Liao, James K
AU  - Liao JK
AD  - Department of Biological Sciences Division-Cardiology, University of Chicago, 
      USA.
FAU - Wu, Rongxue
AU  - Wu R
AUID- ORCID: 0000-0003-4857-4655
AD  - Department of Biological Sciences Division-Cardiology, University of Chicago, 
      USA.
LA  - eng
GR  - P30 DK020595/DK/NIDDK NIH HHS/United States
GR  - R01 HL136962/HL/NHLBI NIH HHS/United States
GR  - R01 HL140114/HL/NHLBI NIH HHS/United States
GR  - T32 HL007381/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20210330
PL  - United States
TA  - Oxid Med Cell Longev
JT  - Oxidative medicine and cellular longevity
JID - 101479826
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tight Junction Proteins)
RN  - CYS9AKD70P (Isoflurane)
RN  - EC 3.4.24.17 (MMP3 protein, human)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - EC 3.4.24.17 (Mmp3 protein, mouse)
SB  - IM
MH  - Animals
MH  - Blood-Brain Barrier/enzymology/*metabolism
MH  - Brain/blood supply
MH  - Endothelial Cells/cytology/metabolism
MH  - Humans
MH  - Isoflurane/pharmacokinetics/pharmacology
MH  - *MAP Kinase Signaling System
MH  - Matrix Metalloproteinase 3/deficiency/*metabolism/pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Recombinant Proteins/pharmacology
MH  - Tight Junction Proteins/metabolism
PMC - PMC8026308
COIS- The authors declare that there is no conflict of interest regarding the 
      publication of this article.
EDAT- 2021/04/17 06:00
MHDA- 2021/06/10 06:00
PMCR- 2021/03/30
CRDT- 2021/04/16 06:36
PHST- 2020/10/09 00:00 [received]
PHST- 2020/11/24 00:00 [revised]
PHST- 2021/03/09 00:00 [accepted]
PHST- 2021/04/16 06:36 [entrez]
PHST- 2021/04/17 06:00 [pubmed]
PHST- 2021/06/10 06:00 [medline]
PHST- 2021/03/30 00:00 [pmc-release]
AID - 10.1155/2021/6655122 [doi]
PST - epublish
SO  - Oxid Med Cell Longev. 2021 Mar 30;2021:6655122. doi: 10.1155/2021/6655122. 
      eCollection 2021.