title: Brain pericytes are the most thrombin-sensitive matrix metalloproteinase-9-releasing cell type constituting the blood-brain barrier in vitro.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Machida
authors.affiliation: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan; BBB Laboratory, PharmaCo-Cell Co., Ltd., Nagasaki, Japan.
authors.forename: Fuyuko
authors.initials: F
authors.lastname: Takata
authors.affiliation: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Matsumoto
authors.affiliation: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors.forename: Hisayo
authors.initials: H
authors.lastname: Takenoshita
authors.affiliation: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors.forename: Ikuya
authors.initials: I
authors.lastname: Kimura
authors.affiliation: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamauchi
authors.affiliation: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Dohgu
authors.affiliation: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan; BBB Laboratory, PharmaCo-Cell Co., Ltd., Nagasaki, Japan. Electronic address: ykataoka@fukuoka-u.ac.jp.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000166:cytology* / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000166:cytology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D055806:Microvessels / Q000166:cytology / Q000378:metabolism; D020286:Pericytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D017208:Rats, Wistar; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D044462:Receptors, Proteinase-Activated; D013917:Thrombin; D020780:Matrix Metalloproteinase 9
keywords: Blood–brain barrier; Brain pericytes; Intracerebral hemorrhage; Matrix metalloproteinase-9; Protease-activated receptors; Thrombin