EP4/ANXA2 axis in pulmonary arterial hypertension: therapeutic implications

Abstract 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 PAH progression. Mechanistically, EP4 activation was found to enhance the translation of ANXA2 and phosphorylation of ANXA2 at Thr208 via the cAMP/PKA pathway, promoting PASMC proliferation and migration through increased nuclear translocation of β-catenin, a key signalling molecule in the canonical Wnt pathway. Importantly, pharmacological inhibition or genetic deletion of ANXA2 effectively protected PAH in rodents, suggesting its pathogenic role in PAH development. Conclusions This study reveals a crucial pathway involving EP4 and ANXA2 in PAH development and progression. Targeting EP4 and its downstream effector ANXA2 represents promising therapeutic strategies for PAH management.