Tenascin-C induces prolonged constriction of cerebral arteries in rats

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 10 μg) of TNC were administered intracisternally to healthy rats, and the effects were evaluated by neurobehavioral tests and India-ink angiography at 24, 48, and 72 h after the administration. Western blotting and immunohistochemistry were performed to explore the underlying mechanisms on constricted cerebral arteries after 24 h. 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 24 h. Higher dosages of TNC induced more severe cerebral arterial constriction, which continued for more than 72 h. 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.

► TNC, a matricellular protein, constricted cerebral artery for ≥ 72 h in rats. ► TNC upregulated TLR4 and activated JNK and p38 in the constricted cerebral artery. ► TLR4 antagonists blocked TNC-induced JNK and p38 activation, and vasoconstriction. ► JNK and p38 inhibitors abolished TLR4 upregulation and vasoconstriction by TNC. ► TNC may be involved in the pathogenesis of cerebral vasospasm.