Brain pericytes are the most thrombin-sensitive matrix metalloproteinase-9-releasing cell type constituting the blood–brain barrier in vitro

•Thrombin induced MMP-9 release from brain pericytes.•This MMP-9 release from pericytes was higher than that from other BBB cells.•Pericytes expressed high and moderate levels of PAR1 and PAR4 mRNA, respectively.•PAR1 inhibitor blocked the thrombin-induced MMP-9 release from pericytes.•Thrombin-PAR1...

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Bibliographic Details
Published in:	Neuroscience letters Vol. 599; pp. 109 - 114
Main Authors:	Machida, Takashi, Takata, Fuyuko, Matsumoto, Junichi, Takenoshita, Hisayo, Kimura, Ikuya, Yamauchi, Atsushi, Dohgu, Shinya, Kataoka, Yasufumi
Format:	Journal Article
Language:	English
Published:	Ireland Elsevier B.V 10-07-2015
Subjects:	Animals Astrocytes - drug effects Astrocytes - metabolism Blood-Brain Barrier - cytology Blood-Brain Barrier - metabolism Blood–brain barrier Brain - blood supply Brain - cytology Brain pericytes Endothelial Cells - drug effects Endothelial Cells - metabolism Intracerebral hemorrhage Matrix Metalloproteinase 9 - metabolism Matrix metalloproteinase-9 Microvessels - cytology Microvessels - metabolism Pericytes - cytology Pericytes - drug effects Pericytes - metabolism Protease-activated receptors Rats, Wistar Receptors, Proteinase-Activated - metabolism Thrombin Thrombin - metabolism Thrombin - pharmacology Matrix metalloproteinase-9 Brain pericytes RBECs Thrombin BMECs MMP-9 Intracerebral hemorrhage ICH Blood–brain barrier Protease-activated receptors
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Summary:	•Thrombin induced MMP-9 release from brain pericytes.•This MMP-9 release from pericytes was higher than that from other BBB cells.•Pericytes expressed high and moderate levels of PAR1 and PAR4 mRNA, respectively.•PAR1 inhibitor blocked the thrombin-induced MMP-9 release from pericytes.•Thrombin-PAR1/PAR4 axis in pericytes may mediate ICH-associated BBB disruption. In the acute phase of intracerebral hemorrhage (ICH), hemorrhagic transformation and brain edema are associated with blood–brain barrier (BBB) disruption. Elevated levels of thrombin, a coagulation factor, contribute to the development of brain edema during ICH through matrix metalloproteinase (MMP)-9 production. Thrombin directly induces a variety of cellular responses through its specific receptors known as protease-activated receptors (PARs). However, it remains unclear which cell types constituting the BBB mainly produce MMP-9 in response to thrombin. Here, we compared the MMP-9 release induced by thrombin using primary cultures of rat brain microvascular endothelial cells, astrocytes, and pericytes. Brain pericytes exhibited the highest levels of MMP-9 release due to thrombin stimulation among the BBB cells. The pattern of PAR mRNA expression in pericytes was characterized by high expression of PAR1 and moderate expression of PAR4. Heat-inactivated thrombin failed to stimulate pericytes to release MMP-9. A selective PAR1 inhibitor SCH79797 blocked the thrombin-induced MMP-9 release from pericytes. These findings suggest that both PAR1 and PAR4 mediate thrombin-induced MMP-9 release from pericytes. The present study raises the possibility that brain pericytes could play a pivotal role as a highly thrombin-sensitive and MMP-9-producing cell type at the BBB in brain damage including ICH.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0304-3940 1872-7972
DOI:	10.1016/j.neulet.2015.05.028