EP4/ANXA2 axis in pulmonary arterial hypertension: therapeutic implications

作者：Hu Xu, Lan Ye, Chunxiu Du, Hui Tang, Qi Zheng, Chunhua Zhu, Bo Liang, Yali Wang, Xiuhui Mao, Qing Liang, Jiayao Zhang, Huishu Shao, Xiaowan Sun, Ruqiang Yuan, Weijing Yun, Changbiao Luo, Jiaming Xiu, Wen Su, Fenling Fan, Zhiyu Dai, Lihong Chen, Youfei Guan, Xiaoyan Zhang · 发表于：European Heart Journal · 年份：2025 · DOI：10.1093/eurheartj/ehaf763 · 被引用次数：5 · 研究领域：Pulmonary Hypertension Research and Treatments、Phosphodiesterase function and regulation、Eicosanoids and Hypertension Pharmacology

BACKGROUND AND AIMS: Pulmonary arterial hypertension (PAH) is a progressive condition marked by the abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs), leading to significant remodelling of the pulmonary arteries (PAs). The cyclooxygenase metabolite of arachidonic acid prostaglandin E2 and its receptor EP4 are crucial for maintaining vascular homeostasis. This study aimed to determine the role of EP4 in the pathogenesis of PAH and evaluate the potential of EP4 as a therapeutic target for PAH. METHODS: Two well-established PAH models, the monocrotaline-induced rat model and hypoxia/Su5416-induced mouse model, were used in this study. Both pharmacological interventions (including the EP4 antagonist grapiprant and MF498 and the agonist Cay10598) and genetic strategies (including vascular smooth muscle cell [VSMC]-specific EP4 knockout mice and VSMC-specific human EP4 transgenic mice) were used to comprehensively investigate the role of EP4 in the pathogenesis of PAH. Multiple cellular and molecular biology approaches were employed to investigate the underlying mechanisms. RESULTS: The results showed that the pharmacological blockade of the EP4 receptor and genetic deletion of the EP4 gene in VSMCs led to a significant improvement in PAH and PA remodelling. Conversely, pharmacological activation and VSMC-specific overexpression of EP4 exacerbate PAH progression. Further analysis identified annexin A2 (ANXA2) as a critical downstream mediator in EP4-induced PA...