主动脉夹层是血管生成抑制剂的不良事件，然而，药物与主动脉夹层之间的关联尚不清楚。因此，我们使用药理诱导的易患主动脉夹层模型（LAB）小鼠、培养的内皮细胞和真实世界数据库，采用一种新颖的综合研究方法，研究了血管生成抑制剂如何增加主动脉夹层的发生。我们进行了不对称性分析，并使用世界范围内的自发性不良事件数据库计算并计算报道的比值比作为风险信号，以估计不良事件的风险。血管生成抑制剂，但不是其他高血压诱导药物，对主动脉瘤和夹层显示了显著的风险信号。在日本的医疗收据数据库JMDC进行的回顾性队列分析显示，动脉粥样硬化和血脂异常的历史与血管生成抑制剂使用期间主动脉夹层的发生密切相关，而高血压则不相关。对于体内研究，我们给予LAB小鼠舒尼替尼（每日100mg/kg）的治疗。舒尼替尼使收缩压升高（与无舒尼替尼组相比：182 mmHg vs. 288 mmHg；p＜0.01）并导致主动脉夹层的发生率增加（40% vs. 59%；p = 0.34）。体内和体外研究表明，舒尼替尼增加内皮素-1的表达，并通过细胞内和细胞间黏附分子-1的表达引起内皮细胞损伤。血管生成抑制剂导致主动脉夹层风险增加与特定药物引起的高血压、内皮细胞损伤和内皮素-1表达之间的关联密切相关。我们的研究成果对于建立更安全的抗癌治疗和预防高风险患者血管毒性的发展具有重要价值。版权© 2023 The Authors。由Elsevier Masson SAS出版。保留所有权利。

Aortic dissection is an adverse event of angiogenesis inhibitors; however, the association between the drugs and aortic dissection is unclear. Therefore, we investigated if and how angiogenesis inhibitors increase the onset of aortic dissection using pharmacologically-induced aortic dissection-prone model (LAB) mice, cultured endothelial cells, and real-world databases, which is a novel integrated research approach. Disproportionality analysis was performed and calculated using the reporting odds ratio as a risk signal using a worldwide database of spontaneous adverse events to estimate the risk of adverse events. Angiogenesis inhibitors, but not other hypertension-inducing drugs, showed significant risk signals for aortic aneurysms and dissection. A retrospective cohort analysis using JMDC, a medical receipt database in Japan, showed that the history of atherosclerosis and dyslipidemia, but not hypertension, were significantly associated with the onset of aortic dissection during angiogenesis inhibitor medication administration. For in vivo studies, sunitinib (100 mg/kg/day) was administered to LAB mice. Sunitinib increased systolic blood pressure (182 mmHg vs. 288 mmHg with sunitinib; p＜0.01) and the incidence of aortic dissection (40% vs. 59% with sunitinib; p = 0.34) in mice. In vivo and in vitro studies revealed that sunitinib increased endothelin-1 expression and induced endothelial cell damage evaluated by intracellular- and vascular cell adhesion molecule-1 expressions. The increased risk of developing aortic dissection with angiogenesis inhibitors is associated with the development of drug-specific hypertension via endothelial cell damage and endothelin-1 expression. Our findings are invaluable in establishing safer anticancer therapies and strategies to prevent the development of vascular toxicity in high-risk patients.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.