PVECs‐Derived Exosomal microRNAs Regulate PASMCs via FoxM1 Signaling in IUGR‐induced Pulmonary Hypertension

BACKGROUND: Intrauterine growth restriction (IUGR) is closely related to systemic or pulmonary hypertension (PH) in adulthood. Aberrant crosstalk between pulmonary vascular endothelial cells (PVECs) and pulmonary arterial smooth muscle cells (PASMCs) that is mediated by exosomes plays an essential role in the progression of PH. FoxM1 (Forkhead box M1) is a key transcription factor that governs many important biological processes. METHODS AND RESULTS: IUGR‐induced PH rat models were established. Transwell plates were used to coculture PVECs and PASMCs. Exosomes were isolated from PVEC‐derived medium, and a microRNA (miRNA) screening was proceeded to identify effects of IUGR on small RNAs enclosed within exosomes. Dual‐Luciferase assay was performed to validate the predicted binding sites of miRNAs on FoxM1 3’ untranslated region. FoxM1 inhibitor thiostrepton was used in IUGR‐induced PH rats. In this study, we found that FoxM1 expression was remarkably increased in IUGR‐induced PH, and PASMCs were regulated by PVECs through FoxM1 signaling in a non‐contact way. An miRNA screening showed that miR‐214‐3p, miR‐326‐3p, and miR‐125b‐2‐3p were downregulated in PVEC‐derived exosomes of the IUGR group, which were associated with overexpression of FoxM1 and more significant proliferation and migration of PASMCs. Dual‐Luciferase assay demonstrated that the 3 miRNAs directly targeted FoxM1 3’ untranslated region. FoxM1 inhibition blocked the PVECs‐PASMCs crosstalk and reversed the abnormal functions of PASMCs. In vivo, treatment with thiostrepton significantly reduced the severity of PH. CONCLUSIONS: Transmission of exosomal miRNAs from PVECs regulated the functions of PASMCs via FoxM1 signaling, and FoxM1 may serve as a potential therapeutic target in IUGR‐induced PH.