title: Epidermal growth factor-like repeats of tenascin-C-induced constriction of cerebral arteries via activation of epidermal growth factor receptors in rats.
abstract: Tenascin-C (TNC), one of matricellular proteins, has been suggested to be involved in cerebral vasospasm after aneurysmal subarachnoid hemorrhage. However, the mechanisms of how TNC constricts cerebral arteries remain unclear. The aim of this study was to examine if epidermal growth factor (EGF)-like repeats of TNC is involved in TNC-induced constriction of cerebral arteries in rats via EGF receptor (EGFR) activation. Two dosages of recombinant TNC (r-TNC) consisting of the EGF-like repeats was administered intracisternally to healthy rats, and its vasoconstrictor effects were evaluated by neurobehavioral tests and India-ink angiography at 24, 48, and 72 hours after the administration. Western blotting and immunohistochemistry were performed to explore the underlying mechanisms on constricted cerebral arteries after 24 hours. The effects of a selective EGFR tyrosine kinase inhibitor (AG1478) on r-TNC-induced vasoconstriction were evaluated by neurobehavioral tests, India-ink angiography and immunohistochemistry at 24 hours after the administration. A higher dosage of r-TNC induced cerebral arterial constriction more severely, which continued for 48 hours. The effects were associated with the activation of EGFR and extracellular signal-regulated kinase (ERK)1/2 in the smooth muscle cell layer of the constricted cerebral artery, while c-Jun N-terminal kinase and p38 were not activated. AG1478 blocked r-TNC-induced vasoconstrictive effects, as well as activation of EGFR and ERK1/2. These findings demonstrate that TNC induces constriction of cerebral arteries via activation of EGFR and ERK1/2.
authors.affiliation: Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Shiba
authors.affiliation: Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Kawakita
authors.affiliation: Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Nakasaki
authors.affiliation: Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Shimojo
authors.affiliation: Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan; Research Center for Matrix Biology, Mie University, Tsu, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Imanaka-Yoshida
authors.affiliation: Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan; Research Center for Matrix Biology, Mie University, Tsu, Japan.
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan; Research Center for Matrix Biology, Mie University, Tsu, Japan. Electronic address: suzuki02@clin.medic.mie-u.ac.jp.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D002536:Cerebral Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008297:Male; D023421:Models, Animal; D011799:Quinazolines / Q000494:pharmacology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D019063:Tenascin / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D020301:Vasospasm, Intracranial / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; D011994:Recombinant Proteins; D019063:Tenascin; D020032:Tyrphostins; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Cerebral vasospasm; Epidermal growth factor receptor; Epidermal growth factor-like repeats; Mitogen-activated protein kinase; Tenascin-C