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2014 ; 1593
(ä): 1-8
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p38 MAP kinase mediates transforming-growth factor-?1-induced upregulation of
matrix metalloproteinase-9 but not -2 in human brain pericytes
#MMPMID25451097
Takahashi Y
; Maki T
; Liang AC
; Itoh K
; Lok J
; Osumi N
; Arai K
Brain Res
2014[Dec]; 1593
(ä): 1-8
PMID25451097
show ga
Pericytes are vascular mural cells embedded within the basal lamina of blood
micro-vessels. Within the neurovascular unit, pericytes play important roles in
regulating neurovascular homeostasis by secreting soluble factors, such as matrix
metalloproteinases (MMPs). However, little is known about the regulatory
signaling pathways in brain pericytes. Here we show that transforming growth
factor-?1 (TGF-?1) induces MMP-9 upregulation in pericytes via p38
mitogen-activated protein (MAP) kinase signaling. Cultured human brain vascular
pericytes were used in this study. When the brain pericytes were treated with
purified human TGF-?1 (0.1-10ng/mL for 24h), the levels of MMP-2 and MMP-9 in
culture media were significantly increased in a concentration dependent manner as
measured by gelatin zymography. WST assay confirmed that TGF-?1 did not affect
cell survival of the brain pericytes. A TGF-?-receptor inhibitor SB431542
(0.5-5?M) decreased the TGF-?1-induced upregulation of MMP-2 and MMP-9. To assess
the underlying intracellular mechanisms, we focused on p38 MAP kinase signaling,
which is one of the major downstream kinases for TGF-?1. A well-validated p38 MAP
kinase inhibitor SB203580 (0.5-5?M) cancelled the effect of TGF-?1 in
upregulation of MMP-9 but not MMP-2. Western blotting confirmed that TGF-?1
treatment increased the level of p38 MAP kinase phosphorylation in pericytes, and
again, the TGF-?-receptor inhibitor SB431542 (0.5-5?M) blocked the TGF-?1-induced
phosphorylation of p38 MAP kinase. Both TGF-?1 and MMP-9 are major neurovascular
mediators, and therefore, our current finding may suggest a novel mechanism for
how pericytes regulate neurovascular homeostasis.
|Benzamides/pharmacology
[MESH]
|Brain/drug effects/*metabolism
[MESH]
|Cell Survival/physiology
[MESH]
|Cells, Cultured
[MESH]
|Central Nervous System Agents/pharmacology
[MESH]