Pharmacological Inhibition of Epidermal Growth Factor Receptor Prevents Intracranial Aneurysm Rupture by Reducing Endoplasmic Reticulum Stress.

Document Type

Article

Abstract

BACKGROUND: 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.

METHODS: Using a preclinical mouse model of intracranial aneurysm, we examined the potential roles of EGFR and ER stress in developing aneurysmal rupture.

RESULTS: 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.

CONCLUSIONS: 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.

Keywords

Mice, Animals, Intracranial Aneurysm, Subarachnoid Hemorrhage, Aneurysm, Ruptured, ErbB Receptors, RNA, Messenger, Endoplasmic Reticulum Stress, Inflammation

Medical Subject Headings

Mice; Animals; Intracranial Aneurysm; Subarachnoid Hemorrhage; Aneurysm, Ruptured; ErbB Receptors; RNA, Messenger; Endoplasmic Reticulum Stress; Inflammation

Publication Date

3-1-2024

Publication Title

Hypertension

ISSN

1524-4563

Volume

81

Issue

3

First Page

572

Last Page

581

PubMed ID

38164754

Digital Object Identifier (DOI)

10.1161/HYPERTENSIONAHA.123.21235

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