title: ETB receptor-mediated MMP-9 activation induces vasogenic edema via ZO-1 protein degradation following status epilepticus.
abstract: The blood-brain barrier (BBB) is formed by the endothelial cells with specialized tight junctions (TJs) lining the blood vessels and astroglial endfeet surrounding the blood vessels. Although BBB disruption during brain insults leads to vasogenic edema as one of the primary steps in the epileptogenic process, little is known about the molecular and physiological events concerning vasogenic edema formation. In the present study, status epilepticus (SE) changed the expressions and subcellular localizations of TJ proteins (claudin-5, occludin and zonula occludens-1 (ZO-1)) in endothelial cells of the rat piriform cortex. Among TJ proteins, the alteration in ZO-1 expression was relevant to endothelin B (ETB) receptor-mediated endothelial nitric oxide synthase (eNOS) activation, which increased matrix metalloproteinase-9 (MMP-9) activity. Indeed, BQ788 (an ETB receptor antagonist) effectively attenuated SE-induced vasogenic edema by inhibiting eNOS-mediated MMP-9 activation and ZO-1 protein degradation in endothelial cells, although astroglial endfeet were detached from endothelial cells. Therefore, we suggest that SE-induced ETB receptor/eNOS-mediated MMP-9 activation may lead to impairments of endothelial cell function via TJ protein degradation, which are involved in vasogenic edema formation independent of perivascular astroglial functions.
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon 200-702, South Korea.
authors.forename: J Y
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon 200-702, South Korea.
authors.forename: A-R
authors.initials: AR
authors.lastname: Ko
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon 200-702, South Korea.
authors.forename: H-W
authors.initials: HW
authors.lastname: Hyun
authors.affiliation: Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon 200-702, South Korea. Electronic address: tckang@hallym.ac.kr.
authors.forename: T-C
authors.initials: TC
authors.lastname: Kang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D062507:Claudin-5 / Q000378:metabolism; D004195:Disease Models, Animal; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D062793:Occludin / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D066195:Piriform Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000378:metabolism*; D013226:Status Epilepticus / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism*
chemical_list: D062507:Claudin-5; C491510:Cldn5 protein, rat; D065131:Endothelin B Receptor Antagonists; D018696:Neuroprotective Agents; D062793:Occludin; C568987:Ocln protein, rat; D009842:Oligopeptides; D010880:Piperidines; D044023:Receptor, Endothelin B; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; C086539:BQ 788; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: claudin-5; eNOS; occludin; status epilepticus; vasogenic edema; zonula occludens-1