Cerebral aneurysm progression suppressed by blockage of endothelin B receptor

Nobutake Sadamasa M.D., Ph.D., Kazuhiko Nozaki M.D., Ph.D., Yasushi Takagi M.D., Ph.D., Takuya Moriwaki M.D., Ph.D., Yoshifumi Kawanabe M.D., Ph.D., Masatsune Ishikawa M.D., Ph.D., and Nobuo Hashimoto M.D., Ph.D.
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Object

Cerebral aneurysm is a major cause of subarachnoid hemorrhage, but the mechanisms of its development remain unclear. Mechanical stretch has been reported to induce vascular smooth-muscle cell apoptosis via endothelin B receptors (ETBRs). The objectives of this study were to clarify the expression and localization of ETBR in cerebral aneurysms and to examine the effect of ETBR blockage on the development of experimental cerebral aneurysms.

Methods

Seventy-two rats underwent a cerebral aneurysm induction procedure and were divided into four groups according to the duration of postoperative study periods. Expression of ETBR was confirmed by reverse transcription–polymerase chain reaction and immunohistochemical analysis. The authors also studied the effect of K-8794, an oral selective antagonist of ETBR, to see whether it would influence the formation of cerebral aneurysms.

Two weeks after the aneurysm induction procedure, ETBR was rarely detected in anterior cerebral artery–olfactory artery bifurcations, but it was weakly expressed in experimental cerebral aneurysms at 1 month after the procedure, and markedly expressed at 3 months. The administration of K-8794 for 1 month after the procedure significantly reduced the number of advanced aneurysms and the number of apoptotic smooth-muscle cells.

Conclusions

These results suggest that ETBR might play a significant role in the progression of cerebral aneurysms and have the potential to improve prevention and treatment of cerebral aneurysms.

Abbreviations used in this paper:ACA = anterior cerebral artery; α-SMA = α–smooth muscle actin; BP = blood pressure; ETAR = endothelin A receptor; ETBR = endothelin B receptor; IEL = internal elastic lamina; JNK = c-jun N-terminal protein kinase; MCA = middle cerebral artery; NO = nitric oxide; OA = olfactory artery; PCR = polymerase chain reaction; RT-PCR = reverse transcriptase PCR; ssDNA = single-stranded DNA; VSMC = vascular smooth-muscle cell.

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Contributor Notes

Address reprint requests to: Kazuhiko Nozaki, M.D., Ph.D., Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507 Japan. email: noz@kuhp.kyoto-u.ac.jp.
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