Loss of Endothelin-2 in Pulmonary Neuroendocrine Cells Promotes the Development of Hypoxia-induced Pulmonary Hypertension

Pulmonary hypertension (PH) encompasses a clinical spectrum of diseases with high morbidity and poor survival rates. Over the decades, many studies have reported that endothelin-1 (Edn1) plays a role in several subtypes of PH. However, the beneficial effects of its targeted drugs are only found in patients with group 1 pulmonary arterial hypertension, but not in group 3 PH, which is related to lung diseases and hypoxia. In this study, we revealed contrasting findings for Edn1 and its highly similar peptide Edn2 in hypoxia-induced PH. Edn2 expression exhibited a distinct and transient pattern under hypoxic conditions. Moreover, epithelial cell-specific Edn2-knockout mice showed exacerbated PH phenotypes compared to wild-type mice. We further demonstrated that acute changes in oxygen levels, but not the low-oxygen condition, were pivotal for Edn2 expression regulation, suggesting that Edn2 is involved in oxygen sensing. Supporting these findings, the specific deletion of Edn2 in sensory-specialised lung cells called pulmonary neuroendocrine cells led to an exacerbated PH phenotype. In conclusion, our study revealed a previously unknown protective role of Edn2 in the development of hypoxia-induced PH. Owing to the contradictory findings between Edn1 and Edn2 in the pathogenesis of lung diseases, careful consideration is required when using endothelin receptor antagonists for PH associated with lung disease and hypoxia.