Anti-vasospastic Effects of Epidermal Growth Factor Receptor Inhibitors After Subarachnoid Hemorrhage in Mice
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Subarachnoid hemorrhage (SAH) is a devastating disease. Cerebral vasospasm is still an important cause of post-SAH poor outcomes, but its mechanisms remain unveiled. Activation of epidermal growth factor receptor (EGFR) is suggested to cause vasoconstriction in vitro, but no report has demonstrated the involvement of EGFR in vasospasm development after SAH in vivo. Cross-talk of EGFR and vascular endothelial growth factor (VEGF) receptor, which may affect post-SAH vasospasm, was also reported in cancer cells, but has not been demonstrated in post-SAH vasospasm. The aim of this study was to investigate whether EGFR as well as EGFR-VEGF receptor cross-talk engage in the development of cerebral vasospasm in a mouse SAH model. C57BL6 mice underwent endovascular perforation SAH or sham modeling. At 30 min post-modeling, mice were randomly administrated vehicle or 2 doses of selective EGFR inhibitors intracerebroventricularly. A higher dose of the inhibitor significantly prevented post-SAH neurological impairments at 72 h and vasospasm at 24 h associated with suppression of post-SAH activation of EGFR and extracellular signal-regulated kinase (ERK) 1/2 in the cerebral artery wall, especially in the smooth muscle cell layers. Anti-EGFR neutralizing antibody also showed similar effects. However, neither expression levels of VEGF nor activation levels of a major receptor of VEGF, VEGF receptor-2, were affected by SAH and two kinds of EGFR inactivation. Thus, this study first showed that EGFR-ERK1/2 pathways may be involved in post-SAH vasospasm development, and that EGFR-VEGF receptor cross-talk may not play a significant role in the development of vasospasm in mice.
KeywordsEpidermal growth factor receptor Extracellular signal-regulated kinase 1/2 Subarachnoid hemorrhage Vascular endothelial growth factor Vasospasm
We thank Ms. Chiduru Yamamoto-Nakamura (Department of Neurosurgery, Mie University Graduate School of Medicine) for her assistance with administrative support.
This study was funded by a grant-in-aid for Scientific Research from Japan Society for the Promotion of Science to Drs. Suzuki [17K10825] and Shiba [17K16640].
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Research Involving Animals
All procedures were approved by the Animal Ethics Review Committee of Mie University and were carried out according to the institution’s Guidelines for Animal Experiments.
- 4.McGirt MJ, Lynch JR, Blessing R, Warner DS, Friedman AH, Laskowitz DT (2002) Serum von Willebrand factor, matrix metalloproteinase-9, and vascular endothelial growth factor levels predict the onset of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurgery 51:1128–1135PubMedGoogle Scholar
- 8.Fujimoto M, Shiba M, Kawakita F, Liu L, Nakasaki A, Shimojo N, Imanaka-Yoshida K, Yoshida T et al (2016) Epidermal growth factor-like repeats of tenascin-C-induced constriction of cerebral arteries via activation of epidermal growth factor receptors in rats. Brain Res 1642:436–444PubMedGoogle Scholar
- 39.Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I et al (2011) Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol 10:618–625PubMedGoogle Scholar