内质网
表皮生长因子受体
医学
受体
内分泌学
内科学
生物
细胞生物学
作者
Taichi Ishiguro,Hajime Furukawa,Kyle Polen,Yushiro Take,Hiroki Sato,Daisuke Kudo,James A. Morgan,Hiroki Uchikawa,Takuma Maeda,Oscar Cisneros,Redi Rahmani,Jinglu Ai,Satoru Eguchi,Michael T. Lawton,Tomoki Hashimoto
出处
期刊:Hypertension
[Ovid Technologies (Wolters Kluwer)]
日期:2024-03-01
卷期号:81 (3): 572-581
标识
DOI:10.1161/hypertensionaha.123.21235
摘要
Multiple pathways and factors are involved in the rupture of intracranial aneurysms. The EGFR (epidermal growth factor receptor) has been shown to mediate inflammatory vascular diseases, including atherosclerosis and aortic aneurysm. However, the role of EGFR in mediating intracranial aneurysm rupture and its underlying mechanisms have yet to be determined. Emerging evidence indicates that endoplasmic reticulum (ER) stress might be the link between EGFR activation and the resultant inflammation. ER stress is strongly implicated in inflammation and apoptosis of vascular smooth muscle cells, both of which are key components of the pathophysiology of aneurysm rupture. Therefore, we hypothesized that EGFR activation promotes aneurysmal rupture by inducing ER stress.Using a preclinical mouse model of intracranial aneurysm, we examined the potential roles of EGFR and ER stress in developing aneurysmal rupture.Pharmacological inhibition of EGFR markedly decreased the rupture rate of intracranial aneurysms without altering the formation rate. EGFR inhibition also significantly reduced the mRNA (messenger RNA) expression levels of ER-stress markers and inflammatory cytokines in cerebral arteries. Similarly, ER-stress inhibition also significantly decreased the rupture rate. In contrast, ER-stress induction nullified the protective effect of EGFR inhibition on aneurysm rupture.Our data suggest that EGFR activation is an upstream event that contributes to aneurysm rupture via the induction of ER stress. Pharmacological inhibition of EGFR or downstream ER stress may be a promising therapeutic strategy for preventing aneurysm rupture and subarachnoid hemorrhage.
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