Barrow Aneurysm and AVM Research Center, Barrow Neurological Institute, Phoenix, AZ (T.I., H.F., K.P., Y.T., H.S., D.K., J.M., H.U., T.M., O.C., R.R., J.A., M.T.L., T.H.).
Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (S.E.).
Hypertension. 2024 Mar;81(3):572-581. doi: 10.1161/HYPERTENSIONAHA.123.21235. Epub 2024 Jan 2.
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.
颅内动脉瘤的破裂涉及多种途径和因素。表皮生长因子受体（EGFR）已被证明可介导炎症性血管疾病，包括动脉粥样硬化和主动脉瘤。然而，EGFR 在介导颅内动脉瘤破裂及其潜在机制中的作用尚未确定。新出现的证据表明，内质网（ER）应激可能是 EGFR 激活与由此产生的炎症之间的联系。ER 应激强烈参与血管平滑肌细胞的炎症和凋亡，这两者都是动脉瘤破裂病理生理学的关键组成部分。因此，我们假设 EGFR 激活通过诱导 ER 应激促进动脉瘤破裂。
我们使用颅内动脉瘤的临床前小鼠模型，研究了 EGFR 和 ER 应激在发展动脉瘤破裂中的潜在作用。
EGFR 的药理学抑制显著降低了颅内动脉瘤的破裂率，而不改变其形成率。EGFR 抑制还显著降低了脑动脉中 ER 应激标志物和炎症细胞因子的 mRNA（信使 RNA）表达水平。同样，ER 应激抑制也显著降低了破裂率。相比之下，ER 应激诱导使 EGFR 抑制对动脉瘤破裂的保护作用无效。
我们的数据表明，EGFR 激活是导致动脉瘤破裂的上游事件，通过诱导 ER 应激起作用。EGFR 或下游 ER 应激的药理学抑制可能是预防动脉瘤破裂和蛛网膜下腔出血的有前途的治疗策略。
