title: Tenascin-C induces prolonged constriction of cerebral arteries in rats.
abstract: Tenascin-C (TNC), a matricellular protein, is induced in association with cerebral vasospasm after subarachnoid hemorrhage. The aim of this study was to assess the vasoconstrictive effects of TNC and its mechanisms of action on cerebral arteries in vivo. Two dosages (1 and 10μg) of TNC were administered intracisternally to healthy rats, and the effects were evaluated by neurobehavioral tests and India-ink angiography at 24, 48, and 72h after the administration. Western blotting and immunohistochemistry were performed to explore the underlying mechanisms on constricted cerebral arteries after 24h. The effects of toll-like receptor 4 (TLR4) antagonists (LPS-RS), c-Jun N-terminal kinase (JNK), and p38 inhibitors (SP600125 and SB203580) on TNC-induced vasoconstriction were evaluated at 24h. Higher dosages of TNC induced more severe cerebral arterial constriction, which continued for more than 72h. TNC administration also upregulated TLR4, and activated JNK and p38 in the smooth muscle cell layer of the constricted cerebral artery. LPS-RS blocked TNC-induced TLR4 upregulation, JNK and p38 activation, and vasoconstrictive effects. SP600125 and SB203580 abolished TNC-induced TLR4 upregulation and vasoconstrictive effects. TNC may cause prolonged cerebral arterial constriction via TLR4 and activation of JNK and p38, which may upregulate TLR4. These findings suggest that TNC causes cerebral vasospasm and provides a novel therapeutic approach against it.
authors: Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, Japan.
authors: Masashi
authors: M
authors: Fujimoto
authors: Hidenori
authors: H
authors: Suzuki
authors: Masato
authors: M
authors: Shiba
authors: Naoshi
authors: N
authors: Shimojo
authors: Kyoko
authors: K
authors: Imanaka-Yoshida
authors: Toshimichi
authors: T
authors: Yoshida
authors: Kenji
authors: K
authors: Kanamaru
authors: Satoshi
authors: S
authors: Matsushima
authors: Waro
authors: W
authors: Taki
mesh_terms: D000792:Angiography; D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D009422:Nervous System Diseases / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D018709:Statistics, Nonparametric; D019063:Tenascin / Q000633:toxicity*; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D020301:Vasospasm, Intracranial / Q000139:chemically induced* / Q000150:complications; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D019063:Tenascin; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4